Incidence and Characteristics

The noble false widow spider (Steatoda nobilis) is one of the world’s most invasive spider species, having spread across the globe from Madeira and the Canary Islands into the North Atlantic.^1,2Steatoda comprise multiple species of false widow spiders, named for their resemblance to black widow spiders (Latrodectus). The noble false widow spider is the dominant species in buildings in southern Ireland and Great Britain, with a population surge in 2018 that caused multiple temporary school closures in London, England, for fumigation.³ The noble false widow spider was first documented in the United States in Ventura County, California, in 2011, with numerous specimens found in urban areas (eg, in parks, underneath garbage cans) closer to the coastline as well as farther inland. The species may have been introduced to this area by way of Port Hueneme, a city in California with a US naval base with routes to various other military bases in Western Europe.⁴ Given its already rapid expansion outside of the United States with a concurrent rise in bite reports, dermatologists should be familiar with these invasive and potentially dangerous arachnids.

The spread of noble false widow spiders is assisted by their wide range of temperature tolerance and ability to survive for months with little food and no water. They can live for several years, with one report of a noble false widow spider living up to 7 years.⁵ These spiders are found inside homes and buildings year-round, and they prefer to build their webs in an elevated position such as the top corner of a room. Steatoda weave tangle webs with crisscrossing threads that often have a denser middle section.⁵

Noble false widow spiders are sexually dimorphic, with males typically no larger than 1-cm long and females up to 1.4-cm long. They have a dark brown to black thorax and brown abdomen with red-brown legs. Males have brighter cream-colored abdominal markings than females, who lack markings altogether on their distinctive globular abdomen (Figure). The abdominal markings are known to resemble a skull or house.

©ePhotocorp / iStock / Getty Images Plus.

Although noble false widow spiders are not exclusively synanthropic, they can be found in any crevice in homes or other structures where there are humans such as office buildings.^5-7 Up until the last 20 years, reports of bites from noble false widow spiders worldwide were few and far between. In Great Britain, the spiders were first considered to be common in the 1980s, with recent evidence of an urban population boom in the last 5 to 10 years that has coincided with an increase in bite reports.^5,8,9

Clinical Significance

Most bites occur in a defensive manner, such as when humans perform activities that disturb the hiding space, cause vibrations in the web, or compress the body of the arachnid. Most envenomations in Great Britain occur while the individual is in bed, though they also may occur during other activities that disturb the spider, such as moving boxes or putting on a pair of pants.⁵ Occupational exposure to noble false widow spiders may soon be a concern for those involved in construction, carpentry, cleaning, and decorating given their recent invasive spread into the United States.

The venom from these spiders is neurotoxic and cytotoxic, causing moderate to intense pain that may resemble a wasp sting. The incidence of steatodism—which can include symptoms of pain in addition to fever, hypotension, headache, lethargy, nausea, localized diaphoresis, abdominal pain, paresthesias, and malaise—is unknown but reportedly rare.^5,10 There are considerable similarities between Steatoda and true black widow spider venom, which explains the symptom overlap with latrodectism. There are reports of severe debilitation lasting weeks due to pain and decreased affected limb movement after bites from noble false widow spiders.^10-12

Nearly all noble false widow spider bite reports describe immediate pain upon bite/envenomation, which is unlike the delayed pain from a black widow spider bite (after 10 minutes or more).^6,13,14 Erythema and swelling occur around a pale raised site of envenomation lasting up to 72 hours. The bite site may be highly tender and blister or ulcerate, with reports of cellulitis and local skin necrosis.^7,15 Pruritus during this period can be intense, and excoriation increases the risk for complications such as infection. Reports of anaphylaxis following a noble false widow spider bite are rare.^5,16 The incidence of bites may be underreported due to the lack of proper identification of the responsible arachnid for those who do not seek care or require hospitalization, though this is not unique to Steatoda.

There are reports of secondary infection after bites and even cases of limb amputation, septicemia, and death.^14,17 However, it is unknown if noble false widow spiders are vectors for bacteria transmitted during envenomation, and infection likely is secondary to scratching or inadequate wound care.^18,19 Potentially pathogenic bacteria have been isolated from the body surfaces of the noble false widow spider, including Pseudomonas putida, Staphylococcus capitis, and Staphylococcus epidermidis.²⁰ Fortunately, most captured cases (ie, events in which the biting arachnid was properly identified) report symptoms ranging from mild to moderate in severity without the need for hospitalization. A series of 24 reports revealed that all individuals experienced sharp pain upon the initial bite followed by erythema, and 18 of them experienced considerable swelling of the area soon thereafter. One individual experienced temporary paralysis of the affected limb, and 3 individuals experienced hypotension or hypertension in addition to fever, skin necrosis, or cellulitis.¹⁴

Treatment

The envenomation site should be washed with antibacterial soap and warm water and should be kept clean to prevent infection. There is no evidence that tight pressure bandaging of these bite sites will restrict venom flow; because it may worsen pain in the area, pressure bandaging is not recommended. When possible, the arachnid should be collected for identification. Supportive care is warranted for symptoms of pain, erythema, and swelling, with the use of cool compresses, oral pain relievers (eg, nonsteroidal anti-inflammatory drugs, acetaminophen), topical anesthetic (eg, lidocaine), or antihistamines as needed.

Urgent care is warranted for patients who experience severe symptoms of steatodism such as hypertension, lymphadenopathy, paresthesia, or limb paralysis. Limited reports show onset of this distress typically within an hour of envenomation. Treatments analogous to those for latrodectism including muscle relaxers and pain medications have demonstrated rapid attenuation of symptoms upon intramuscular administration of antivenom made from Latrodectus species.^21-23

Signs of infection warrant bacterial culture with antibiotic susceptibilities to ensure adequate treatment.²⁰ Infections from spider bites can present a few days to a week following envenomation. Symptoms may include spreading redness or an enlarging wound site, pus formation, worsening or unrelenting pain after 24 hours, fevers, flulike symptoms, and muscle cramps.

Final Thoughts

Symptoms from noble false widow spider bites range widely from localized pain, swelling, and erythema to ulceration, necrosis, and rarely death related to secondary infection. Because of their invasive spread in Europe and increasing presence in the United States, it is important to be aware of the possibility of noble false widow spider bites to manage reactions that may quickly lead to morbidity.

Incidence and Characteristics

The noble false widow spider (Steatoda nobilis) is one of the world’s most invasive spider species, having spread across the globe from Madeira and the Canary Islands into the North Atlantic.^1,2Steatoda comprise multiple species of false widow spiders, named for their resemblance to black widow spiders (Latrodectus). The noble false widow spider is the dominant species in buildings in southern Ireland and Great Britain, with a population surge in 2018 that caused multiple temporary school closures in London, England, for fumigation.³ The noble false widow spider was first documented in the United States in Ventura County, California, in 2011, with numerous specimens found in urban areas (eg, in parks, underneath garbage cans) closer to the coastline as well as farther inland. The species may have been introduced to this area by way of Port Hueneme, a city in California with a US naval base with routes to various other military bases in Western Europe.⁴ Given its already rapid expansion outside of the United States with a concurrent rise in bite reports, dermatologists should be familiar with these invasive and potentially dangerous arachnids.

The spread of noble false widow spiders is assisted by their wide range of temperature tolerance and ability to survive for months with little food and no water. They can live for several years, with one report of a noble false widow spider living up to 7 years.⁵ These spiders are found inside homes and buildings year-round, and they prefer to build their webs in an elevated position such as the top corner of a room. Steatoda weave tangle webs with crisscrossing threads that often have a denser middle section.⁵

Noble false widow spiders are sexually dimorphic, with males typically no larger than 1-cm long and females up to 1.4-cm long. They have a dark brown to black thorax and brown abdomen with red-brown legs. Males have brighter cream-colored abdominal markings than females, who lack markings altogether on their distinctive globular abdomen (Figure). The abdominal markings are known to resemble a skull or house.

©ePhotocorp / iStock / Getty Images Plus.

Although noble false widow spiders are not exclusively synanthropic, they can be found in any crevice in homes or other structures where there are humans such as office buildings.^5-7 Up until the last 20 years, reports of bites from noble false widow spiders worldwide were few and far between. In Great Britain, the spiders were first considered to be common in the 1980s, with recent evidence of an urban population boom in the last 5 to 10 years that has coincided with an increase in bite reports.^5,8,9

Clinical Significance

Most bites occur in a defensive manner, such as when humans perform activities that disturb the hiding space, cause vibrations in the web, or compress the body of the arachnid. Most envenomations in Great Britain occur while the individual is in bed, though they also may occur during other activities that disturb the spider, such as moving boxes or putting on a pair of pants.⁵ Occupational exposure to noble false widow spiders may soon be a concern for those involved in construction, carpentry, cleaning, and decorating given their recent invasive spread into the United States.

The venom from these spiders is neurotoxic and cytotoxic, causing moderate to intense pain that may resemble a wasp sting. The incidence of steatodism—which can include symptoms of pain in addition to fever, hypotension, headache, lethargy, nausea, localized diaphoresis, abdominal pain, paresthesias, and malaise—is unknown but reportedly rare.^5,10 There are considerable similarities between Steatoda and true black widow spider venom, which explains the symptom overlap with latrodectism. There are reports of severe debilitation lasting weeks due to pain and decreased affected limb movement after bites from noble false widow spiders.^10-12

Nearly all noble false widow spider bite reports describe immediate pain upon bite/envenomation, which is unlike the delayed pain from a black widow spider bite (after 10 minutes or more).^6,13,14 Erythema and swelling occur around a pale raised site of envenomation lasting up to 72 hours. The bite site may be highly tender and blister or ulcerate, with reports of cellulitis and local skin necrosis.^7,15 Pruritus during this period can be intense, and excoriation increases the risk for complications such as infection. Reports of anaphylaxis following a noble false widow spider bite are rare.^5,16 The incidence of bites may be underreported due to the lack of proper identification of the responsible arachnid for those who do not seek care or require hospitalization, though this is not unique to Steatoda.

There are reports of secondary infection after bites and even cases of limb amputation, septicemia, and death.^14,17 However, it is unknown if noble false widow spiders are vectors for bacteria transmitted during envenomation, and infection likely is secondary to scratching or inadequate wound care.^18,19 Potentially pathogenic bacteria have been isolated from the body surfaces of the noble false widow spider, including Pseudomonas putida, Staphylococcus capitis, and Staphylococcus epidermidis.²⁰ Fortunately, most captured cases (ie, events in which the biting arachnid was properly identified) report symptoms ranging from mild to moderate in severity without the need for hospitalization. A series of 24 reports revealed that all individuals experienced sharp pain upon the initial bite followed by erythema, and 18 of them experienced considerable swelling of the area soon thereafter. One individual experienced temporary paralysis of the affected limb, and 3 individuals experienced hypotension or hypertension in addition to fever, skin necrosis, or cellulitis.¹⁴

Treatment

The envenomation site should be washed with antibacterial soap and warm water and should be kept clean to prevent infection. There is no evidence that tight pressure bandaging of these bite sites will restrict venom flow; because it may worsen pain in the area, pressure bandaging is not recommended. When possible, the arachnid should be collected for identification. Supportive care is warranted for symptoms of pain, erythema, and swelling, with the use of cool compresses, oral pain relievers (eg, nonsteroidal anti-inflammatory drugs, acetaminophen), topical anesthetic (eg, lidocaine), or antihistamines as needed.

Urgent care is warranted for patients who experience severe symptoms of steatodism such as hypertension, lymphadenopathy, paresthesia, or limb paralysis. Limited reports show onset of this distress typically within an hour of envenomation. Treatments analogous to those for latrodectism including muscle relaxers and pain medications have demonstrated rapid attenuation of symptoms upon intramuscular administration of antivenom made from Latrodectus species.^21-23

Signs of infection warrant bacterial culture with antibiotic susceptibilities to ensure adequate treatment.²⁰ Infections from spider bites can present a few days to a week following envenomation. Symptoms may include spreading redness or an enlarging wound site, pus formation, worsening or unrelenting pain after 24 hours, fevers, flulike symptoms, and muscle cramps.

Final Thoughts

Symptoms from noble false widow spider bites range widely from localized pain, swelling, and erythema to ulceration, necrosis, and rarely death related to secondary infection. Because of their invasive spread in Europe and increasing presence in the United States, it is important to be aware of the possibility of noble false widow spider bites to manage reactions that may quickly lead to morbidity.

Incidence and Characteristics

The noble false widow spider (Steatoda nobilis) is one of the world’s most invasive spider species, having spread across the globe from Madeira and the Canary Islands into the North Atlantic.^1,2Steatoda comprise multiple species of false widow spiders, named for their resemblance to black widow spiders (Latrodectus). The noble false widow spider is the dominant species in buildings in southern Ireland and Great Britain, with a population surge in 2018 that caused multiple temporary school closures in London, England, for fumigation.³ The noble false widow spider was first documented in the United States in Ventura County, California, in 2011, with numerous specimens found in urban areas (eg, in parks, underneath garbage cans) closer to the coastline as well as farther inland. The species may have been introduced to this area by way of Port Hueneme, a city in California with a US naval base with routes to various other military bases in Western Europe.⁴ Given its already rapid expansion outside of the United States with a concurrent rise in bite reports, dermatologists should be familiar with these invasive and potentially dangerous arachnids.

The spread of noble false widow spiders is assisted by their wide range of temperature tolerance and ability to survive for months with little food and no water. They can live for several years, with one report of a noble false widow spider living up to 7 years.⁵ These spiders are found inside homes and buildings year-round, and they prefer to build their webs in an elevated position such as the top corner of a room. Steatoda weave tangle webs with crisscrossing threads that often have a denser middle section.⁵

Noble false widow spiders are sexually dimorphic, with males typically no larger than 1-cm long and females up to 1.4-cm long. They have a dark brown to black thorax and brown abdomen with red-brown legs. Males have brighter cream-colored abdominal markings than females, who lack markings altogether on their distinctive globular abdomen (Figure). The abdominal markings are known to resemble a skull or house.

©ePhotocorp / iStock / Getty Images Plus.

Although noble false widow spiders are not exclusively synanthropic, they can be found in any crevice in homes or other structures where there are humans such as office buildings.^5-7 Up until the last 20 years, reports of bites from noble false widow spiders worldwide were few and far between. In Great Britain, the spiders were first considered to be common in the 1980s, with recent evidence of an urban population boom in the last 5 to 10 years that has coincided with an increase in bite reports.^5,8,9

Clinical Significance

Most bites occur in a defensive manner, such as when humans perform activities that disturb the hiding space, cause vibrations in the web, or compress the body of the arachnid. Most envenomations in Great Britain occur while the individual is in bed, though they also may occur during other activities that disturb the spider, such as moving boxes or putting on a pair of pants.⁵ Occupational exposure to noble false widow spiders may soon be a concern for those involved in construction, carpentry, cleaning, and decorating given their recent invasive spread into the United States.

The venom from these spiders is neurotoxic and cytotoxic, causing moderate to intense pain that may resemble a wasp sting. The incidence of steatodism—which can include symptoms of pain in addition to fever, hypotension, headache, lethargy, nausea, localized diaphoresis, abdominal pain, paresthesias, and malaise—is unknown but reportedly rare.^5,10 There are considerable similarities between Steatoda and true black widow spider venom, which explains the symptom overlap with latrodectism. There are reports of severe debilitation lasting weeks due to pain and decreased affected limb movement after bites from noble false widow spiders.^10-12

Nearly all noble false widow spider bite reports describe immediate pain upon bite/envenomation, which is unlike the delayed pain from a black widow spider bite (after 10 minutes or more).^6,13,14 Erythema and swelling occur around a pale raised site of envenomation lasting up to 72 hours. The bite site may be highly tender and blister or ulcerate, with reports of cellulitis and local skin necrosis.^7,15 Pruritus during this period can be intense, and excoriation increases the risk for complications such as infection. Reports of anaphylaxis following a noble false widow spider bite are rare.^5,16 The incidence of bites may be underreported due to the lack of proper identification of the responsible arachnid for those who do not seek care or require hospitalization, though this is not unique to Steatoda.

There are reports of secondary infection after bites and even cases of limb amputation, septicemia, and death.^14,17 However, it is unknown if noble false widow spiders are vectors for bacteria transmitted during envenomation, and infection likely is secondary to scratching or inadequate wound care.^18,19 Potentially pathogenic bacteria have been isolated from the body surfaces of the noble false widow spider, including Pseudomonas putida, Staphylococcus capitis, and Staphylococcus epidermidis.²⁰ Fortunately, most captured cases (ie, events in which the biting arachnid was properly identified) report symptoms ranging from mild to moderate in severity without the need for hospitalization. A series of 24 reports revealed that all individuals experienced sharp pain upon the initial bite followed by erythema, and 18 of them experienced considerable swelling of the area soon thereafter. One individual experienced temporary paralysis of the affected limb, and 3 individuals experienced hypotension or hypertension in addition to fever, skin necrosis, or cellulitis.¹⁴

Treatment

The envenomation site should be washed with antibacterial soap and warm water and should be kept clean to prevent infection. There is no evidence that tight pressure bandaging of these bite sites will restrict venom flow; because it may worsen pain in the area, pressure bandaging is not recommended. When possible, the arachnid should be collected for identification. Supportive care is warranted for symptoms of pain, erythema, and swelling, with the use of cool compresses, oral pain relievers (eg, nonsteroidal anti-inflammatory drugs, acetaminophen), topical anesthetic (eg, lidocaine), or antihistamines as needed.

Urgent care is warranted for patients who experience severe symptoms of steatodism such as hypertension, lymphadenopathy, paresthesia, or limb paralysis. Limited reports show onset of this distress typically within an hour of envenomation. Treatments analogous to those for latrodectism including muscle relaxers and pain medications have demonstrated rapid attenuation of symptoms upon intramuscular administration of antivenom made from Latrodectus species.^21-23

Signs of infection warrant bacterial culture with antibiotic susceptibilities to ensure adequate treatment.²⁰ Infections from spider bites can present a few days to a week following envenomation. Symptoms may include spreading redness or an enlarging wound site, pus formation, worsening or unrelenting pain after 24 hours, fevers, flulike symptoms, and muscle cramps.

Final Thoughts

Symptoms from noble false widow spider bites range widely from localized pain, swelling, and erythema to ulceration, necrosis, and rarely death related to secondary infection. Because of their invasive spread in Europe and increasing presence in the United States, it is important to be aware of the possibility of noble false widow spider bites to manage reactions that may quickly lead to morbidity.

The short-form video hosting service TikTok has become a mainstream platform for individuals to share their ideas and educate the public regarding dermatologic diseases such as atopic dermatitis, alopecia, and acne. Users can create and post videos, leave comments, and indicate their interest in or approval of certain content by “liking” videos. In 2022, according to a Pew Research Center survey, approximately 67% of American teenagers aged 13 to 17 years reported using TikTok at least once.¹ This population, along with the rest of its users, are increasing their use of TikTok to share information on dermatologic topics such as acne and isotretinoin.^2,3 Spironolactone is an effective medication for acne but is not as widely known to the public as other acne medications such as retinoids, salicylic acid, and benzoyl peroxide. Being aware of youth exposure to media related to acne and spironolactone can help dermatologists understand gaps in education and refine their interactions with this patient population.

To gain insight into youth exposure to spironolactone, we conducted a search of TikTok on July 26, 2022, using the term #spironolactone to retrieve the top 50 videos identified by TikTok under the “Top” tab on spironolactone. Search results and the top 10 comments for each video were reviewed. The total number of views and likes for the top 50 videos were 6,735,992 and 851,856, respectively.

Videos were subdivided into educational information related to spironolactone and/or skin care (32% [16/50]), discussion of side effects of spironolactone (26% [13/50]), those with noticeable improvement of acne following treatment with spironolactone (20% [10/50]), recommendations to see a physician or dermatologist to treat acne (10% [5/50]), and other (12% [6/50]). Other takeaways from the top 50 videos included the following:

• Common side effects: irregular periods (10% [5/50]), frequent urination (8% [4/50]), dizziness/lightheadedness (8% [4/50]), and breast tenderness (6% [3/50])
• Longest reported use of spironolactone: 4 years, with complete acne resolution
• Average treatment length prior to noticeable results: 4 to 6 months, with the shortest being 1 month
• Reported dosages of spironolactone: ranged from 50 to 200 mg/d. The most common dosage was 100 mg/d (10% [5/50]). The lowest reported dosage was 50 mg/d (4% [2/50]), while the highest reported dosage was 200 mg/d (2% [1/50])
• Self-reported concurrent use of spironolactone with a combined oral contraceptive: drospirenoneTimes New Roman–ethinyl estradiol (4% [2/50]), norethindrone acetateTimes New Roman–ethinyl estradiol/ferrous fumarate (2% [1/50]), and norgestimateTimes New Roman–ethinyl estradiol (2% [1/50])
• Negative experiences with side effects and lack of acne improvement that led to treatment cessation: 8% (4/50).

Even though spironolactone is not as well-known as other treatments for acne, we found many TikTok users posting about, commenting on, and highlighting the relevance of this therapeutic option. There was no suggestion in any of the videos that spironolactone could be obtained without physician care and/or prescription. A prior report discussing youth sentiment of isotretinoin use on TikTok found that popular videos and videos with the most likes focused on the drug’s positive impact on acne improvement, while comments displayed heightened desires to learn more about isotretinoin and its side effects.³ Our analysis showed a similar response to spironolactone. In all videos showcasing the skin before and after treatment, there were noticeable improvements in the poster’s acne. Most of the video comments displayed a desire to learn more about spironolactone and its side effects. There also were many questions about time to noticeable results. In contrast to the study on isotretinoin,³ the most-liked spironolactone videos contained educational information about spironolactone and/or skin care rather than focusing solely on the impact of the drug on acne. Additionally, the study on isotretinoin found no videos mentioning the importance of seeing a dermatologist or other health care professional,³ while our search found multiple videos (10% [5/50]) on spironolactone that advised seeking physician help. In fact, several popular videos (8% [4/50]) were created by board-certified dermatologists who mainly focused on providing educational information. This difference in educational content may be attributed to spironolactone’s lesser-known function in treating acne. Furthermore, the comments suggested a growing interest in learning more about spironolactone as a treatment option for acne, specifically its mechanism of action and side effects.

With nearly 2 billion monthly active users globally and 94.1 million monthly active users in the United States (as of March 2023),⁴ TikTok is a popular social media platform that allows dermatologists to better understand youth sentiment on acne treatments such as spironolactone and isotretinoin and also provides an opportunity for medical education to reach a larger audience. This increased youth insight from TikTok can be utilized by dermatologists to make more informed decisions in developing patient-centered care that appeals to the adolescent population.

The short-form video hosting service TikTok has become a mainstream platform for individuals to share their ideas and educate the public regarding dermatologic diseases such as atopic dermatitis, alopecia, and acne. Users can create and post videos, leave comments, and indicate their interest in or approval of certain content by “liking” videos. In 2022, according to a Pew Research Center survey, approximately 67% of American teenagers aged 13 to 17 years reported using TikTok at least once.¹ This population, along with the rest of its users, are increasing their use of TikTok to share information on dermatologic topics such as acne and isotretinoin.^2,3 Spironolactone is an effective medication for acne but is not as widely known to the public as other acne medications such as retinoids, salicylic acid, and benzoyl peroxide. Being aware of youth exposure to media related to acne and spironolactone can help dermatologists understand gaps in education and refine their interactions with this patient population.

To gain insight into youth exposure to spironolactone, we conducted a search of TikTok on July 26, 2022, using the term #spironolactone to retrieve the top 50 videos identified by TikTok under the “Top” tab on spironolactone. Search results and the top 10 comments for each video were reviewed. The total number of views and likes for the top 50 videos were 6,735,992 and 851,856, respectively.

Videos were subdivided into educational information related to spironolactone and/or skin care (32% [16/50]), discussion of side effects of spironolactone (26% [13/50]), those with noticeable improvement of acne following treatment with spironolactone (20% [10/50]), recommendations to see a physician or dermatologist to treat acne (10% [5/50]), and other (12% [6/50]). Other takeaways from the top 50 videos included the following:

• Common side effects: irregular periods (10% [5/50]), frequent urination (8% [4/50]), dizziness/lightheadedness (8% [4/50]), and breast tenderness (6% [3/50])
• Longest reported use of spironolactone: 4 years, with complete acne resolution
• Average treatment length prior to noticeable results: 4 to 6 months, with the shortest being 1 month
• Reported dosages of spironolactone: ranged from 50 to 200 mg/d. The most common dosage was 100 mg/d (10% [5/50]). The lowest reported dosage was 50 mg/d (4% [2/50]), while the highest reported dosage was 200 mg/d (2% [1/50])
• Self-reported concurrent use of spironolactone with a combined oral contraceptive: drospirenoneTimes New Roman–ethinyl estradiol (4% [2/50]), norethindrone acetateTimes New Roman–ethinyl estradiol/ferrous fumarate (2% [1/50]), and norgestimateTimes New Roman–ethinyl estradiol (2% [1/50])
• Negative experiences with side effects and lack of acne improvement that led to treatment cessation: 8% (4/50).

Even though spironolactone is not as well-known as other treatments for acne, we found many TikTok users posting about, commenting on, and highlighting the relevance of this therapeutic option. There was no suggestion in any of the videos that spironolactone could be obtained without physician care and/or prescription. A prior report discussing youth sentiment of isotretinoin use on TikTok found that popular videos and videos with the most likes focused on the drug’s positive impact on acne improvement, while comments displayed heightened desires to learn more about isotretinoin and its side effects.³ Our analysis showed a similar response to spironolactone. In all videos showcasing the skin before and after treatment, there were noticeable improvements in the poster’s acne. Most of the video comments displayed a desire to learn more about spironolactone and its side effects. There also were many questions about time to noticeable results. In contrast to the study on isotretinoin,³ the most-liked spironolactone videos contained educational information about spironolactone and/or skin care rather than focusing solely on the impact of the drug on acne. Additionally, the study on isotretinoin found no videos mentioning the importance of seeing a dermatologist or other health care professional,³ while our search found multiple videos (10% [5/50]) on spironolactone that advised seeking physician help. In fact, several popular videos (8% [4/50]) were created by board-certified dermatologists who mainly focused on providing educational information. This difference in educational content may be attributed to spironolactone’s lesser-known function in treating acne. Furthermore, the comments suggested a growing interest in learning more about spironolactone as a treatment option for acne, specifically its mechanism of action and side effects.

With nearly 2 billion monthly active users globally and 94.1 million monthly active users in the United States (as of March 2023),⁴ TikTok is a popular social media platform that allows dermatologists to better understand youth sentiment on acne treatments such as spironolactone and isotretinoin and also provides an opportunity for medical education to reach a larger audience. This increased youth insight from TikTok can be utilized by dermatologists to make more informed decisions in developing patient-centered care that appeals to the adolescent population.

The short-form video hosting service TikTok has become a mainstream platform for individuals to share their ideas and educate the public regarding dermatologic diseases such as atopic dermatitis, alopecia, and acne. Users can create and post videos, leave comments, and indicate their interest in or approval of certain content by “liking” videos. In 2022, according to a Pew Research Center survey, approximately 67% of American teenagers aged 13 to 17 years reported using TikTok at least once.¹ This population, along with the rest of its users, are increasing their use of TikTok to share information on dermatologic topics such as acne and isotretinoin.^2,3 Spironolactone is an effective medication for acne but is not as widely known to the public as other acne medications such as retinoids, salicylic acid, and benzoyl peroxide. Being aware of youth exposure to media related to acne and spironolactone can help dermatologists understand gaps in education and refine their interactions with this patient population.

To gain insight into youth exposure to spironolactone, we conducted a search of TikTok on July 26, 2022, using the term #spironolactone to retrieve the top 50 videos identified by TikTok under the “Top” tab on spironolactone. Search results and the top 10 comments for each video were reviewed. The total number of views and likes for the top 50 videos were 6,735,992 and 851,856, respectively.

Videos were subdivided into educational information related to spironolactone and/or skin care (32% [16/50]), discussion of side effects of spironolactone (26% [13/50]), those with noticeable improvement of acne following treatment with spironolactone (20% [10/50]), recommendations to see a physician or dermatologist to treat acne (10% [5/50]), and other (12% [6/50]). Other takeaways from the top 50 videos included the following:

• Common side effects: irregular periods (10% [5/50]), frequent urination (8% [4/50]), dizziness/lightheadedness (8% [4/50]), and breast tenderness (6% [3/50])
• Longest reported use of spironolactone: 4 years, with complete acne resolution
• Average treatment length prior to noticeable results: 4 to 6 months, with the shortest being 1 month
• Reported dosages of spironolactone: ranged from 50 to 200 mg/d. The most common dosage was 100 mg/d (10% [5/50]). The lowest reported dosage was 50 mg/d (4% [2/50]), while the highest reported dosage was 200 mg/d (2% [1/50])
• Self-reported concurrent use of spironolactone with a combined oral contraceptive: drospirenoneTimes New Roman–ethinyl estradiol (4% [2/50]), norethindrone acetateTimes New Roman–ethinyl estradiol/ferrous fumarate (2% [1/50]), and norgestimateTimes New Roman–ethinyl estradiol (2% [1/50])
• Negative experiences with side effects and lack of acne improvement that led to treatment cessation: 8% (4/50).

Even though spironolactone is not as well-known as other treatments for acne, we found many TikTok users posting about, commenting on, and highlighting the relevance of this therapeutic option. There was no suggestion in any of the videos that spironolactone could be obtained without physician care and/or prescription. A prior report discussing youth sentiment of isotretinoin use on TikTok found that popular videos and videos with the most likes focused on the drug’s positive impact on acne improvement, while comments displayed heightened desires to learn more about isotretinoin and its side effects.³ Our analysis showed a similar response to spironolactone. In all videos showcasing the skin before and after treatment, there were noticeable improvements in the poster’s acne. Most of the video comments displayed a desire to learn more about spironolactone and its side effects. There also were many questions about time to noticeable results. In contrast to the study on isotretinoin,³ the most-liked spironolactone videos contained educational information about spironolactone and/or skin care rather than focusing solely on the impact of the drug on acne. Additionally, the study on isotretinoin found no videos mentioning the importance of seeing a dermatologist or other health care professional,³ while our search found multiple videos (10% [5/50]) on spironolactone that advised seeking physician help. In fact, several popular videos (8% [4/50]) were created by board-certified dermatologists who mainly focused on providing educational information. This difference in educational content may be attributed to spironolactone’s lesser-known function in treating acne. Furthermore, the comments suggested a growing interest in learning more about spironolactone as a treatment option for acne, specifically its mechanism of action and side effects.

With nearly 2 billion monthly active users globally and 94.1 million monthly active users in the United States (as of March 2023),⁴ TikTok is a popular social media platform that allows dermatologists to better understand youth sentiment on acne treatments such as spironolactone and isotretinoin and also provides an opportunity for medical education to reach a larger audience. This increased youth insight from TikTok can be utilized by dermatologists to make more informed decisions in developing patient-centered care that appeals to the adolescent population.

Practice Gap

Pain and anxiety are common in fully conscious patients undergoing dermatologic surgery with local anesthesia. Particularly during nail surgery, pain from anesthetic injection—caused by both needle insertion and fluid infiltration—occurs because the nail unit is highly vascularized and innervated.¹ Current methods to improve patient comfort during infiltration include use of a buffered anesthetic solution, warming the anesthetic, slower technique, and direct cold application.²

Perioperative anxiety correlates with increased postoperative pain, analgesic use, and delayed recovery. Furthermore, increased perioperative anxiety reduces the pain threshold and elevates estimates of pain intensity.³ Therefore, reducing procedure-related anxiety and pain may improve quality of care and ease patient discomfort.

Distraction is a common and practical nonpharmacotherapeutic technique for reducing pain and anxiety during medical procedures. The refocusing method of distraction aims to divert attention away from pain to more pleasant stimuli to reduce pain perception.³ Several methods of distraction—using stress balls, engaging in conversation, hand-holding, applying virtual reality, and playing videos—can decrease perioperative anxiety and pain.^3-6

Procedural pain and distraction techniques have been evaluated in the pediatric population more than in adults.⁴ Nail surgery–associated pain and distraction techniques for nail surgery have been inadequately studied.⁷

We offer a distraction technique utilizing a portable massager to ensure that patients are as comfortable as possible when the local anesthetic is injected prior to the first incision.

The Technique

A portable shiatsu massager that uses heat and deep-tissue kneading is placed on the upper thigh for toenail cases or lower arm for fingernail cases during injection of anesthetic to divert the patient’s attention from the surgical site (Figure). Kneading from the massage helps distract the patient from pain by introducing a competing, more pleasant, vibrating sensation that overrides pain signals; the relaxation component helps to diminish patient anxiety during injection.

Practice Implications

Use of a portable massager may reduce pain through both distraction and vibration. In a randomized clinical trial of 115 patients undergoing hand or facial surgery, patients who viewed a distraction video during the procedure reported a lower pain score compared to the control group (mean [SD] visual analog scale of pain score, 3.4 [2.6] vs 4.5 [2.6][P=.01]).⁴ In another randomized clinical trial of 25 patients undergoing lip augmentation, 92% of patients (23/25) in the vibration-assisted arm endorsed less pain during procedures compared to the arm without vibration (mean [SD] pain score, 3.82 [1.73] vs 5.6 [1.76][P<.001]).⁸

Utilization of a portable massager is a safe means of improving the patient experience; the distracting and relaxing effects and intense pulsations simultaneously reduce anxiety and pain during nail surgery. Controlled clinical trials are needed to evaluate its efficacy in diminishing both anxiety and pain during nail procedures compared to other analgesic methods.

Practice Gap

Pain and anxiety are common in fully conscious patients undergoing dermatologic surgery with local anesthesia. Particularly during nail surgery, pain from anesthetic injection—caused by both needle insertion and fluid infiltration—occurs because the nail unit is highly vascularized and innervated.¹ Current methods to improve patient comfort during infiltration include use of a buffered anesthetic solution, warming the anesthetic, slower technique, and direct cold application.²

Perioperative anxiety correlates with increased postoperative pain, analgesic use, and delayed recovery. Furthermore, increased perioperative anxiety reduces the pain threshold and elevates estimates of pain intensity.³ Therefore, reducing procedure-related anxiety and pain may improve quality of care and ease patient discomfort.

Distraction is a common and practical nonpharmacotherapeutic technique for reducing pain and anxiety during medical procedures. The refocusing method of distraction aims to divert attention away from pain to more pleasant stimuli to reduce pain perception.³ Several methods of distraction—using stress balls, engaging in conversation, hand-holding, applying virtual reality, and playing videos—can decrease perioperative anxiety and pain.^3-6

Procedural pain and distraction techniques have been evaluated in the pediatric population more than in adults.⁴ Nail surgery–associated pain and distraction techniques for nail surgery have been inadequately studied.⁷

We offer a distraction technique utilizing a portable massager to ensure that patients are as comfortable as possible when the local anesthetic is injected prior to the first incision.

The Technique

A portable shiatsu massager that uses heat and deep-tissue kneading is placed on the upper thigh for toenail cases or lower arm for fingernail cases during injection of anesthetic to divert the patient’s attention from the surgical site (Figure). Kneading from the massage helps distract the patient from pain by introducing a competing, more pleasant, vibrating sensation that overrides pain signals; the relaxation component helps to diminish patient anxiety during injection.

Practice Implications

Use of a portable massager may reduce pain through both distraction and vibration. In a randomized clinical trial of 115 patients undergoing hand or facial surgery, patients who viewed a distraction video during the procedure reported a lower pain score compared to the control group (mean [SD] visual analog scale of pain score, 3.4 [2.6] vs 4.5 [2.6][P=.01]).⁴ In another randomized clinical trial of 25 patients undergoing lip augmentation, 92% of patients (23/25) in the vibration-assisted arm endorsed less pain during procedures compared to the arm without vibration (mean [SD] pain score, 3.82 [1.73] vs 5.6 [1.76][P<.001]).⁸

Utilization of a portable massager is a safe means of improving the patient experience; the distracting and relaxing effects and intense pulsations simultaneously reduce anxiety and pain during nail surgery. Controlled clinical trials are needed to evaluate its efficacy in diminishing both anxiety and pain during nail procedures compared to other analgesic methods.

Practice Gap

Pain and anxiety are common in fully conscious patients undergoing dermatologic surgery with local anesthesia. Particularly during nail surgery, pain from anesthetic injection—caused by both needle insertion and fluid infiltration—occurs because the nail unit is highly vascularized and innervated.¹ Current methods to improve patient comfort during infiltration include use of a buffered anesthetic solution, warming the anesthetic, slower technique, and direct cold application.²

Perioperative anxiety correlates with increased postoperative pain, analgesic use, and delayed recovery. Furthermore, increased perioperative anxiety reduces the pain threshold and elevates estimates of pain intensity.³ Therefore, reducing procedure-related anxiety and pain may improve quality of care and ease patient discomfort.

Distraction is a common and practical nonpharmacotherapeutic technique for reducing pain and anxiety during medical procedures. The refocusing method of distraction aims to divert attention away from pain to more pleasant stimuli to reduce pain perception.³ Several methods of distraction—using stress balls, engaging in conversation, hand-holding, applying virtual reality, and playing videos—can decrease perioperative anxiety and pain.^3-6

Procedural pain and distraction techniques have been evaluated in the pediatric population more than in adults.⁴ Nail surgery–associated pain and distraction techniques for nail surgery have been inadequately studied.⁷

We offer a distraction technique utilizing a portable massager to ensure that patients are as comfortable as possible when the local anesthetic is injected prior to the first incision.

The Technique

A portable shiatsu massager that uses heat and deep-tissue kneading is placed on the upper thigh for toenail cases or lower arm for fingernail cases during injection of anesthetic to divert the patient’s attention from the surgical site (Figure). Kneading from the massage helps distract the patient from pain by introducing a competing, more pleasant, vibrating sensation that overrides pain signals; the relaxation component helps to diminish patient anxiety during injection.

Practice Implications

Use of a portable massager may reduce pain through both distraction and vibration. In a randomized clinical trial of 115 patients undergoing hand or facial surgery, patients who viewed a distraction video during the procedure reported a lower pain score compared to the control group (mean [SD] visual analog scale of pain score, 3.4 [2.6] vs 4.5 [2.6][P=.01]).⁴ In another randomized clinical trial of 25 patients undergoing lip augmentation, 92% of patients (23/25) in the vibration-assisted arm endorsed less pain during procedures compared to the arm without vibration (mean [SD] pain score, 3.82 [1.73] vs 5.6 [1.76][P<.001]).⁸

Utilization of a portable massager is a safe means of improving the patient experience; the distracting and relaxing effects and intense pulsations simultaneously reduce anxiety and pain during nail surgery. Controlled clinical trials are needed to evaluate its efficacy in diminishing both anxiety and pain during nail procedures compared to other analgesic methods.

FLOTCH (leukonychia totalis-trichilemmal cysts-ciliary dystrophy syndrome) syndrome is a rare genetic cutaneous disorder primarily characterized by multiple recurrent trichilemmal pilar cysts and leukonychia. It may be associated with ciliary dystrophy, koilonychia, and/or less frequently renal calculi and pancreatitis. This disorder often presents in an autosomal-dominant pattern of inheritance. Leukonychia and associated pilar cysts originally were termed Bauer syndrome in 1920 and later described in 1986 as FLOTCH syndrome secondary to the association with ciliary dystrophy. ^1,2 The term FLOTCH was coined by Friedel et al ¹ to describe a combination of diagnoses experienced by a family in which several members had multiple pilar cysts, leukonychia, and ciliary dystrophy. We present a 25-year-old Black woman with suspected FLOTCH syndrome who was seen in our clinic for enlarging cysts. 

Case Report

A 25-year-old Black woman with no notable medical history presented to the clinic for a surgical evaluation of cysts of several years’ duration that were enlarging and tender. Physical examination revealed multiple firm, fixed, tender nodules on the left superior parietal scalp, left inferior frontal scalp (Figure 1A), right inferior parietal scalp, right central postauricular skin, and right inferior occipital scalp. Similar-appearing cysts measuring 1.5 to 2 cm were seen on the left rib cage (Figure 1B) and left lateral forearm. Upon further examination, there was homogeneous, nonblanchable, white discoloration of all 10 fingernails consistent with true leukonychia (Figure 1C). When questioned about the nails, the patient stated they had been this color her whole life. Moreover, the patient confirmed that her brother’s nails had a similar appearance.

The patient subsequently underwent elliptical excision of the cysts located on the left medial forehead and left rib cage, and histopathology revealed trichilemmal pilar cysts with dystrophic calcification, dermal fibrosis, and mild chronic inflammation (Figure 2). The pathology report also noted that the anatomic site was somewhat unusual; however, the features were otherwise typical and diagnostic. Given the presentation of multiple pilar cysts throughout the body, leukonychia totalis, and positive family history, the patient was diagnosed with FLOTCH syndrome. Unfortunately, the patient was lost to follow-up following the excision, and no further management could be provided.

Comment

Leukonychia is an abnormality of the nail that results in a visible distribution of white color across the nail plate. It can be classified as totalis when covering the entire nail or partialis when covering localized areas of the nail. The disease also is categorized as acquired or inherited. Acquired leukonychia may appear after damage to a particular area of the nail or secondary to an underlying systemic disease, clinically appearing as white puncta or transverse striae. Hereditary leukonychia is rare, primarily covering the entire nail (totalis), and often is inherited in an autosomal-dominant pattern.^3,4 The appearance of this disease can be an isolated occurrence or may be a component of a condition such as FLOTCH syndrome, as proposed in this case.

Pilar cysts (also known as trichilemmal cysts) are benign, slowly growing, firm, subcutaneous nodules that are similar to epidermoid cysts but arise from the root sheaths of hair follicles. Pilar cysts are inherited in an autosomal-dominant pattern and are caused by a mutation involving a 2-hit mechanism of variants of the phospholipase C delta 1 gene, PLCD1. Patients typically present with multiple cysts,⁵ as in our case.

This association of leukonychia and multiple pilar cysts previously has been reported in 7 family lines.^1-3,6-9 The molecular basis of FLOTCH syndrome is unknown, and these combined diagnoses may be of syndromic nature. Histologic observations of leukonychia and the mechanism of the creation of pilar cysts suggest derivation from similar abnormal keratinization in the nail beds and hair follicles, respectively.⁶

The first familial association between leukonychia totalis and sebaceous cysts was described by Bauer² in 1920. In 1975, Bushkell and Gorlin⁷ reported a similar inherited association with the addition of a history of renal calculi. In 1986, Friedel et al¹ coined the term FLOTCH syndrome when reporting a case of an affected family presenting with leukonychia, recurrent cysts, and ciliary dystrophy. Slee et al⁸ reported 2 cases of pancreatitis experienced by patients presenting with these cysts and leukonychia. The etiology of the pancreatitis was unknown, leading researchers to believe it may be a complication associated with the spectrum of diseases.⁸ In 2008, Morin et al⁶ proposed that those with linked leukonychia and trichilemmal cysts may be at risk for neuromas or spinal tumors and suggested systematic screening after observing a family member with an ependymoma and bilateral multiple acoustic tumors. Rodríguez-Lojo et al³ described a 5-generation family with leukonychia totalis and numerous pilar cysts. Mutoh et al⁹ reported another 5-generation family with associated leukonychia and multiple pilar cysts as well as koilonychia. One family member had a reported history of renal calculus.⁹

In our case, FLOTCH syndrome was suspected given the patient’s concurrent pilar and follicular infundibular cysts. No specific treatment was indicated; however, as seen in prior cases and in ours, many patients prefer to have the cysts excised. A more comprehensive investigation could have revealed other associations, such as ciliary dystrophy, renal calculi, or pancreatitis. It is possible that in conjunction with the syndrome, patients could develop other such clinical manifestations. Pilar cysts most frequently are found on the scalp, yet in patients with concurrent leukonychia, the cysts have been shown to also develop in other regions of the body, as seen in our patient and in the case reported by Mutoh et al.⁹ Given the autosomal-dominant nature of this disease and the keratinizing structures affected, we confer with the hypotheses that a general keratin dysfunction is suspected. Further investigation is needed to determine the exact altered genetic mechanism or deficiency that may be causing this abnormal keratinization as well as a more extensive examination of patients to confirm if other described symptoms may be related.

FLOTCH (leukonychia totalis-trichilemmal cysts-ciliary dystrophy syndrome) syndrome is a rare genetic cutaneous disorder primarily characterized by multiple recurrent trichilemmal pilar cysts and leukonychia. It may be associated with ciliary dystrophy, koilonychia, and/or less frequently renal calculi and pancreatitis. This disorder often presents in an autosomal-dominant pattern of inheritance. Leukonychia and associated pilar cysts originally were termed Bauer syndrome in 1920 and later described in 1986 as FLOTCH syndrome secondary to the association with ciliary dystrophy. ^1,2 The term FLOTCH was coined by Friedel et al ¹ to describe a combination of diagnoses experienced by a family in which several members had multiple pilar cysts, leukonychia, and ciliary dystrophy. We present a 25-year-old Black woman with suspected FLOTCH syndrome who was seen in our clinic for enlarging cysts. 

Case Report

A 25-year-old Black woman with no notable medical history presented to the clinic for a surgical evaluation of cysts of several years’ duration that were enlarging and tender. Physical examination revealed multiple firm, fixed, tender nodules on the left superior parietal scalp, left inferior frontal scalp (Figure 1A), right inferior parietal scalp, right central postauricular skin, and right inferior occipital scalp. Similar-appearing cysts measuring 1.5 to 2 cm were seen on the left rib cage (Figure 1B) and left lateral forearm. Upon further examination, there was homogeneous, nonblanchable, white discoloration of all 10 fingernails consistent with true leukonychia (Figure 1C). When questioned about the nails, the patient stated they had been this color her whole life. Moreover, the patient confirmed that her brother’s nails had a similar appearance.

The patient subsequently underwent elliptical excision of the cysts located on the left medial forehead and left rib cage, and histopathology revealed trichilemmal pilar cysts with dystrophic calcification, dermal fibrosis, and mild chronic inflammation (Figure 2). The pathology report also noted that the anatomic site was somewhat unusual; however, the features were otherwise typical and diagnostic. Given the presentation of multiple pilar cysts throughout the body, leukonychia totalis, and positive family history, the patient was diagnosed with FLOTCH syndrome. Unfortunately, the patient was lost to follow-up following the excision, and no further management could be provided.

Comment

Leukonychia is an abnormality of the nail that results in a visible distribution of white color across the nail plate. It can be classified as totalis when covering the entire nail or partialis when covering localized areas of the nail. The disease also is categorized as acquired or inherited. Acquired leukonychia may appear after damage to a particular area of the nail or secondary to an underlying systemic disease, clinically appearing as white puncta or transverse striae. Hereditary leukonychia is rare, primarily covering the entire nail (totalis), and often is inherited in an autosomal-dominant pattern.^3,4 The appearance of this disease can be an isolated occurrence or may be a component of a condition such as FLOTCH syndrome, as proposed in this case.

Pilar cysts (also known as trichilemmal cysts) are benign, slowly growing, firm, subcutaneous nodules that are similar to epidermoid cysts but arise from the root sheaths of hair follicles. Pilar cysts are inherited in an autosomal-dominant pattern and are caused by a mutation involving a 2-hit mechanism of variants of the phospholipase C delta 1 gene, PLCD1. Patients typically present with multiple cysts,⁵ as in our case.

This association of leukonychia and multiple pilar cysts previously has been reported in 7 family lines.^1-3,6-9 The molecular basis of FLOTCH syndrome is unknown, and these combined diagnoses may be of syndromic nature. Histologic observations of leukonychia and the mechanism of the creation of pilar cysts suggest derivation from similar abnormal keratinization in the nail beds and hair follicles, respectively.⁶

The first familial association between leukonychia totalis and sebaceous cysts was described by Bauer² in 1920. In 1975, Bushkell and Gorlin⁷ reported a similar inherited association with the addition of a history of renal calculi. In 1986, Friedel et al¹ coined the term FLOTCH syndrome when reporting a case of an affected family presenting with leukonychia, recurrent cysts, and ciliary dystrophy. Slee et al⁸ reported 2 cases of pancreatitis experienced by patients presenting with these cysts and leukonychia. The etiology of the pancreatitis was unknown, leading researchers to believe it may be a complication associated with the spectrum of diseases.⁸ In 2008, Morin et al⁶ proposed that those with linked leukonychia and trichilemmal cysts may be at risk for neuromas or spinal tumors and suggested systematic screening after observing a family member with an ependymoma and bilateral multiple acoustic tumors. Rodríguez-Lojo et al³ described a 5-generation family with leukonychia totalis and numerous pilar cysts. Mutoh et al⁹ reported another 5-generation family with associated leukonychia and multiple pilar cysts as well as koilonychia. One family member had a reported history of renal calculus.⁹

In our case, FLOTCH syndrome was suspected given the patient’s concurrent pilar and follicular infundibular cysts. No specific treatment was indicated; however, as seen in prior cases and in ours, many patients prefer to have the cysts excised. A more comprehensive investigation could have revealed other associations, such as ciliary dystrophy, renal calculi, or pancreatitis. It is possible that in conjunction with the syndrome, patients could develop other such clinical manifestations. Pilar cysts most frequently are found on the scalp, yet in patients with concurrent leukonychia, the cysts have been shown to also develop in other regions of the body, as seen in our patient and in the case reported by Mutoh et al.⁹ Given the autosomal-dominant nature of this disease and the keratinizing structures affected, we confer with the hypotheses that a general keratin dysfunction is suspected. Further investigation is needed to determine the exact altered genetic mechanism or deficiency that may be causing this abnormal keratinization as well as a more extensive examination of patients to confirm if other described symptoms may be related.

FLOTCH (leukonychia totalis-trichilemmal cysts-ciliary dystrophy syndrome) syndrome is a rare genetic cutaneous disorder primarily characterized by multiple recurrent trichilemmal pilar cysts and leukonychia. It may be associated with ciliary dystrophy, koilonychia, and/or less frequently renal calculi and pancreatitis. This disorder often presents in an autosomal-dominant pattern of inheritance. Leukonychia and associated pilar cysts originally were termed Bauer syndrome in 1920 and later described in 1986 as FLOTCH syndrome secondary to the association with ciliary dystrophy. ^1,2 The term FLOTCH was coined by Friedel et al ¹ to describe a combination of diagnoses experienced by a family in which several members had multiple pilar cysts, leukonychia, and ciliary dystrophy. We present a 25-year-old Black woman with suspected FLOTCH syndrome who was seen in our clinic for enlarging cysts. 

Case Report

A 25-year-old Black woman with no notable medical history presented to the clinic for a surgical evaluation of cysts of several years’ duration that were enlarging and tender. Physical examination revealed multiple firm, fixed, tender nodules on the left superior parietal scalp, left inferior frontal scalp (Figure 1A), right inferior parietal scalp, right central postauricular skin, and right inferior occipital scalp. Similar-appearing cysts measuring 1.5 to 2 cm were seen on the left rib cage (Figure 1B) and left lateral forearm. Upon further examination, there was homogeneous, nonblanchable, white discoloration of all 10 fingernails consistent with true leukonychia (Figure 1C). When questioned about the nails, the patient stated they had been this color her whole life. Moreover, the patient confirmed that her brother’s nails had a similar appearance.

The patient subsequently underwent elliptical excision of the cysts located on the left medial forehead and left rib cage, and histopathology revealed trichilemmal pilar cysts with dystrophic calcification, dermal fibrosis, and mild chronic inflammation (Figure 2). The pathology report also noted that the anatomic site was somewhat unusual; however, the features were otherwise typical and diagnostic. Given the presentation of multiple pilar cysts throughout the body, leukonychia totalis, and positive family history, the patient was diagnosed with FLOTCH syndrome. Unfortunately, the patient was lost to follow-up following the excision, and no further management could be provided.

Comment

Leukonychia is an abnormality of the nail that results in a visible distribution of white color across the nail plate. It can be classified as totalis when covering the entire nail or partialis when covering localized areas of the nail. The disease also is categorized as acquired or inherited. Acquired leukonychia may appear after damage to a particular area of the nail or secondary to an underlying systemic disease, clinically appearing as white puncta or transverse striae. Hereditary leukonychia is rare, primarily covering the entire nail (totalis), and often is inherited in an autosomal-dominant pattern.^3,4 The appearance of this disease can be an isolated occurrence or may be a component of a condition such as FLOTCH syndrome, as proposed in this case.

Pilar cysts (also known as trichilemmal cysts) are benign, slowly growing, firm, subcutaneous nodules that are similar to epidermoid cysts but arise from the root sheaths of hair follicles. Pilar cysts are inherited in an autosomal-dominant pattern and are caused by a mutation involving a 2-hit mechanism of variants of the phospholipase C delta 1 gene, PLCD1. Patients typically present with multiple cysts,⁵ as in our case.

This association of leukonychia and multiple pilar cysts previously has been reported in 7 family lines.^1-3,6-9 The molecular basis of FLOTCH syndrome is unknown, and these combined diagnoses may be of syndromic nature. Histologic observations of leukonychia and the mechanism of the creation of pilar cysts suggest derivation from similar abnormal keratinization in the nail beds and hair follicles, respectively.⁶

The first familial association between leukonychia totalis and sebaceous cysts was described by Bauer² in 1920. In 1975, Bushkell and Gorlin⁷ reported a similar inherited association with the addition of a history of renal calculi. In 1986, Friedel et al¹ coined the term FLOTCH syndrome when reporting a case of an affected family presenting with leukonychia, recurrent cysts, and ciliary dystrophy. Slee et al⁸ reported 2 cases of pancreatitis experienced by patients presenting with these cysts and leukonychia. The etiology of the pancreatitis was unknown, leading researchers to believe it may be a complication associated with the spectrum of diseases.⁸ In 2008, Morin et al⁶ proposed that those with linked leukonychia and trichilemmal cysts may be at risk for neuromas or spinal tumors and suggested systematic screening after observing a family member with an ependymoma and bilateral multiple acoustic tumors. Rodríguez-Lojo et al³ described a 5-generation family with leukonychia totalis and numerous pilar cysts. Mutoh et al⁹ reported another 5-generation family with associated leukonychia and multiple pilar cysts as well as koilonychia. One family member had a reported history of renal calculus.⁹

In our case, FLOTCH syndrome was suspected given the patient’s concurrent pilar and follicular infundibular cysts. No specific treatment was indicated; however, as seen in prior cases and in ours, many patients prefer to have the cysts excised. A more comprehensive investigation could have revealed other associations, such as ciliary dystrophy, renal calculi, or pancreatitis. It is possible that in conjunction with the syndrome, patients could develop other such clinical manifestations. Pilar cysts most frequently are found on the scalp, yet in patients with concurrent leukonychia, the cysts have been shown to also develop in other regions of the body, as seen in our patient and in the case reported by Mutoh et al.⁹ Given the autosomal-dominant nature of this disease and the keratinizing structures affected, we confer with the hypotheses that a general keratin dysfunction is suspected. Further investigation is needed to determine the exact altered genetic mechanism or deficiency that may be causing this abnormal keratinization as well as a more extensive examination of patients to confirm if other described symptoms may be related.

Dermatology residency positions continue to be highly coveted among applicants in the match. In 2019, dermatology proved to be the most competitive specialty, with 36.3% of US medical school seniors and independent applicants going unmatched.¹ Prior to the transition to a pass/fail system, the mean US Medical Licensing Examination (USMLE) Step 1 score for matched applicants increased from 247 in 2014 to 251 in 2019. The growing number of scholarly activities reported by applicants has contributed to the competitiveness of the specialty. In 2018, the mean number of abstracts, presentations, and publications reported by matched applicants was 14.71, which was higher than other competitive specialties, including orthopedic surgery and otolaryngology (11.5 and 10.4, respectively). Dermatology applicants who did not match in 2018 reported a mean of 8.6 abstracts, presentations, and publications, which was on par with successful applicants in many other specialties.¹ In 2011, Stratman and Ness² found that publishing manuscripts and listing research experience were factors strongly associated with matching into dermatology for reapplicants. These trends in reported research have added pressure for applicants to increase their publications.

Given that many students do not choose a career in dermatology until later in medical school, some students choose to take a gap year between their third and fourth years of medical school to pursue a research fellowship (RF) and produce publications, in theory to increase the chances of matching in dermatology. A survey of dermatology applicants conducted by Costello et al³ in 2021 found that, of the students who completed a gap year (n=90; 31.25%), 78.7% (n=71) of them completed an RF, and those who completed RFs were more likely to match at top dermatology residency programs (P<.01). The authors also reported that there was no significant difference in overall match rates between gap-year and non–gap-year applicants.³ Another survey of 328 medical students found that the most common reason students take years off for research during medical school is to increase competitiveness for residency application.⁴ Although it is clear that students completing an RF often find success in the match, there are limited published data on how those involved in selecting dermatology residents view this additional year. We surveyed faculty members participating in the resident selection process to assess their viewpoints on how RFs factored into an applicant’s odds of matching into dermatology residency and performance as a resident.

Materials and Methods

An institutional review board application was submitted through the Geisinger Health System (Danville, Pennsylvania), and an exemption to complete the survey was granted. The survey consisted of 16 questions via REDCap electronic data capture and was sent to a listserve of dermatology program directors who were asked to distribute the survey to program chairs and faculty members within their department. Survey questions evaluated the participants’ involvement in medical student advising and the residency selection process. Questions relating to the respondents’ opinions were based on a 5-point Likert scale on level of agreement (1=strongly agree; 5=strongly disagree) or importance (1=a great deal; 5=not at all). All responses were collected anonymously. Data points were compiled and analyzed using REDCap. Statistical analysis via χ² tests were conducted when appropriate.

Results

The survey was sent to 142 individuals and distributed to faculty members within those departments between August 16, 2019, and September 24, 2019. The survey elicited a total of 110 respondents. Demographic information is shown in eTable 1. Of these respondents, 35.5% were program directors, 23.6% were program chairs, 3.6% were both program director and program chair, and 37.3% were core faculty members. Although respondents’ roles were varied, 96.4% indicated that they were involved in both advising medical students and in selecting residents.

None of the respondents indicated that they always recommend that students complete an RF, and only 4.5% indicated that they usually recommend it; 40% of respondents rarely or never recommend an RF, while 55.5% sometimes recommend it. Although there was a variety of responses to how frequently faculty members recommend an RF, almost all respondents (98.2%) agreed that the reason medical students pursued an RF prior to residency application was to increase the competitiveness of their residency application. However, 20% of respondents believed that students in this cohort were seeking to gain a deeper understanding of the specialty, and 27.3% thought that this cohort had genuine interest in research. Interestingly, despite the medical students’ intentions of choosing an RF, most respondents (67.3%) agreed or strongly agreed that the publications produced by fellows make an impact on the dermatologic scientific community.

Although some respondents indicated that completion of an RF positively impacts resident performance with regard to patient care, most indicated that the impact was a little (26.4%) or not at all (50%). Additionally, a minority of respondents (11.8%) believed that RFs positively impact resident performance on in-service and board examinations at least a moderate amount, with 62.7% indicating no positive impact at all. Only 12.7% of participants agreed or strongly agreed that completion of an RF led to increased applicant involvement in research throughout their career, and most (73.6%) believed there were downsides to completing an RF. Finally, only 20% agreed or strongly agreed that students who completed an RF were more dedicated to the field of dermatology (eTable 2).

Further evaluation of the data indicated that the perceived utility of RFs did not affect respondents’ recommendation on whether to pursue an RF or not. For example, of the 4.5% of respondents who indicated that they always or usually recommended RFs, only 1 respondent believed that students who completed an RF were more dedicated to the field of dermatology than those who did not. Although 55.5% of respondents answered that they sometimes recommended completion of an RF, less than a quarter of this group believed that students who completed an RF were more likely to be heavily involved in research throughout their career (P=.99).

Overall, 11.8% of respondents indicated that completion of a dermatology RF influenced the evaluation of an applicant a great deal or a lot, while 53.6% of respondents indicated a little or no influence at all. Most respondents (62.8%) agreed or strongly agreed that completion of an RF can compensate for flaws in a residency application. Furthermore, when asked if completion of an RF could set 2 otherwise equivocal applicants apart from one another, 46.4% of respondents agreed or strongly agreed with the statement, while only 17.3% disagreed or strongly disagreed (eTable 2).

Comment

This study characterized how completion of an RF is viewed by those involved in advising medical students and selecting dermatology residents. The growing pressure for applicants to increase the number of publications combined with the competitiveness of applying for a dermatology residency position has led to increased participation in RFs. However, studies have found that students who completed an RF often did so despite a lack of interest.⁴ Nonetheless, little is known about how this is perceived by those involved in choosing residents.

We found that few respondents always or usually advised applicants to complete an RF, but the majority sometimes recommended them, demonstrating the complexity of this issue. Completion of an RF impacted 11.8% of respondents’ overall opinion of an applicant a lot or a great deal, while most respondents (53.6%) were influenced a little or not at all. However, 46.4% of respondents indicated that completion of a dermatology RF would set apart 2 applicants of otherwise equal standing, and 62.8% agreed or strongly agreed that completion of an RF would compensate for flaws in an application. These responses align with the findings of a study conducted by Kaffenberger et al,⁵ who surveyed members of the Association of Professors of Dermatology and found that 74.5% (73/98) of mentors almost always or sometimes recommended a research gap year for reasons that included low grades, low USMLE Step scores, and little research. These data suggest that completion of an RF can give a competitive advantage to applicants despite most advisors acknowledging that these applicants are not likely to be involved in research throughout their careers, perform better on standardized examinations, or provide better patient care.

Given the complexity of this issue, respondents may not have been able to accurately answer the question about how much an RF influenced their overall opinion of an applicant because of subconscious bias. Furthermore, respondents likely tailored their recommendations to complete an RF based on individual applicant strengths and weaknesses, and the specific reasons why one may recommend an RF need to be further investigated.

Although there may be other perceived advantages to RFs that were not captured by our survey, completion of a dermatology RF is not without disadvantages. Fellowships often are unfunded and offered in cities with high costs of living. Additionally, students are forced to delay graduation from medical school by a year at minimum and continue to accrue interest on medical school loans during this time. The financial burdens of completing an RF may exclude students of lower socioeconomic status and contribute to a decrease in diversity within the field. Dermatology has been found to be the second least diverse specialty, behind orthopedics.⁶ Soliman et al⁷ found that racial minorities and low-income students were more likely to cite socioeconomic barriers as factors involved in their decision not to pursue a career in dermatology. This notion was supported by Rinderknecht et al,⁸ who found that Black and Latinx dermatology applicants were more likely to come from disadvantaged backgrounds, and Black applicants were more likely to indicate financial concerns as their primary reason for not pursuing an RF. The impact of accumulated student debt and decreased access should be carefully weighed against the potential benefits of an RF. However, as the USMLE transitions their Step 1 score reporting from numerical to a pass/fail system, it also is possible that dermatology programs will place more emphasis on research productivity when evaluating applications for residency. Overall, the decision to recommend an RF represents an extremely complex topic, as indicated by the results of this study.

Limitations—Our survey-based study is limited by response rate and response bias. Despite the large number of responses, the overall response rate cannot be determined because it is unknown how many total faculty members actually received the survey. Moreover, data collected from current dermatology residents who have completed RFs vs those who have not as they pertain to resident performance and preparedness for the rigors of a dermatology residency would be useful.

Dermatology residency positions continue to be highly coveted among applicants in the match. In 2019, dermatology proved to be the most competitive specialty, with 36.3% of US medical school seniors and independent applicants going unmatched.¹ Prior to the transition to a pass/fail system, the mean US Medical Licensing Examination (USMLE) Step 1 score for matched applicants increased from 247 in 2014 to 251 in 2019. The growing number of scholarly activities reported by applicants has contributed to the competitiveness of the specialty. In 2018, the mean number of abstracts, presentations, and publications reported by matched applicants was 14.71, which was higher than other competitive specialties, including orthopedic surgery and otolaryngology (11.5 and 10.4, respectively). Dermatology applicants who did not match in 2018 reported a mean of 8.6 abstracts, presentations, and publications, which was on par with successful applicants in many other specialties.¹ In 2011, Stratman and Ness² found that publishing manuscripts and listing research experience were factors strongly associated with matching into dermatology for reapplicants. These trends in reported research have added pressure for applicants to increase their publications.

Given that many students do not choose a career in dermatology until later in medical school, some students choose to take a gap year between their third and fourth years of medical school to pursue a research fellowship (RF) and produce publications, in theory to increase the chances of matching in dermatology. A survey of dermatology applicants conducted by Costello et al³ in 2021 found that, of the students who completed a gap year (n=90; 31.25%), 78.7% (n=71) of them completed an RF, and those who completed RFs were more likely to match at top dermatology residency programs (P<.01). The authors also reported that there was no significant difference in overall match rates between gap-year and non–gap-year applicants.³ Another survey of 328 medical students found that the most common reason students take years off for research during medical school is to increase competitiveness for residency application.⁴ Although it is clear that students completing an RF often find success in the match, there are limited published data on how those involved in selecting dermatology residents view this additional year. We surveyed faculty members participating in the resident selection process to assess their viewpoints on how RFs factored into an applicant’s odds of matching into dermatology residency and performance as a resident.

Materials and Methods

An institutional review board application was submitted through the Geisinger Health System (Danville, Pennsylvania), and an exemption to complete the survey was granted. The survey consisted of 16 questions via REDCap electronic data capture and was sent to a listserve of dermatology program directors who were asked to distribute the survey to program chairs and faculty members within their department. Survey questions evaluated the participants’ involvement in medical student advising and the residency selection process. Questions relating to the respondents’ opinions were based on a 5-point Likert scale on level of agreement (1=strongly agree; 5=strongly disagree) or importance (1=a great deal; 5=not at all). All responses were collected anonymously. Data points were compiled and analyzed using REDCap. Statistical analysis via χ² tests were conducted when appropriate.

Results

The survey was sent to 142 individuals and distributed to faculty members within those departments between August 16, 2019, and September 24, 2019. The survey elicited a total of 110 respondents. Demographic information is shown in eTable 1. Of these respondents, 35.5% were program directors, 23.6% were program chairs, 3.6% were both program director and program chair, and 37.3% were core faculty members. Although respondents’ roles were varied, 96.4% indicated that they were involved in both advising medical students and in selecting residents.

None of the respondents indicated that they always recommend that students complete an RF, and only 4.5% indicated that they usually recommend it; 40% of respondents rarely or never recommend an RF, while 55.5% sometimes recommend it. Although there was a variety of responses to how frequently faculty members recommend an RF, almost all respondents (98.2%) agreed that the reason medical students pursued an RF prior to residency application was to increase the competitiveness of their residency application. However, 20% of respondents believed that students in this cohort were seeking to gain a deeper understanding of the specialty, and 27.3% thought that this cohort had genuine interest in research. Interestingly, despite the medical students’ intentions of choosing an RF, most respondents (67.3%) agreed or strongly agreed that the publications produced by fellows make an impact on the dermatologic scientific community.

Although some respondents indicated that completion of an RF positively impacts resident performance with regard to patient care, most indicated that the impact was a little (26.4%) or not at all (50%). Additionally, a minority of respondents (11.8%) believed that RFs positively impact resident performance on in-service and board examinations at least a moderate amount, with 62.7% indicating no positive impact at all. Only 12.7% of participants agreed or strongly agreed that completion of an RF led to increased applicant involvement in research throughout their career, and most (73.6%) believed there were downsides to completing an RF. Finally, only 20% agreed or strongly agreed that students who completed an RF were more dedicated to the field of dermatology (eTable 2).

Further evaluation of the data indicated that the perceived utility of RFs did not affect respondents’ recommendation on whether to pursue an RF or not. For example, of the 4.5% of respondents who indicated that they always or usually recommended RFs, only 1 respondent believed that students who completed an RF were more dedicated to the field of dermatology than those who did not. Although 55.5% of respondents answered that they sometimes recommended completion of an RF, less than a quarter of this group believed that students who completed an RF were more likely to be heavily involved in research throughout their career (P=.99).

Overall, 11.8% of respondents indicated that completion of a dermatology RF influenced the evaluation of an applicant a great deal or a lot, while 53.6% of respondents indicated a little or no influence at all. Most respondents (62.8%) agreed or strongly agreed that completion of an RF can compensate for flaws in a residency application. Furthermore, when asked if completion of an RF could set 2 otherwise equivocal applicants apart from one another, 46.4% of respondents agreed or strongly agreed with the statement, while only 17.3% disagreed or strongly disagreed (eTable 2).

Comment

This study characterized how completion of an RF is viewed by those involved in advising medical students and selecting dermatology residents. The growing pressure for applicants to increase the number of publications combined with the competitiveness of applying for a dermatology residency position has led to increased participation in RFs. However, studies have found that students who completed an RF often did so despite a lack of interest.⁴ Nonetheless, little is known about how this is perceived by those involved in choosing residents.

We found that few respondents always or usually advised applicants to complete an RF, but the majority sometimes recommended them, demonstrating the complexity of this issue. Completion of an RF impacted 11.8% of respondents’ overall opinion of an applicant a lot or a great deal, while most respondents (53.6%) were influenced a little or not at all. However, 46.4% of respondents indicated that completion of a dermatology RF would set apart 2 applicants of otherwise equal standing, and 62.8% agreed or strongly agreed that completion of an RF would compensate for flaws in an application. These responses align with the findings of a study conducted by Kaffenberger et al,⁵ who surveyed members of the Association of Professors of Dermatology and found that 74.5% (73/98) of mentors almost always or sometimes recommended a research gap year for reasons that included low grades, low USMLE Step scores, and little research. These data suggest that completion of an RF can give a competitive advantage to applicants despite most advisors acknowledging that these applicants are not likely to be involved in research throughout their careers, perform better on standardized examinations, or provide better patient care.

Given the complexity of this issue, respondents may not have been able to accurately answer the question about how much an RF influenced their overall opinion of an applicant because of subconscious bias. Furthermore, respondents likely tailored their recommendations to complete an RF based on individual applicant strengths and weaknesses, and the specific reasons why one may recommend an RF need to be further investigated.

Although there may be other perceived advantages to RFs that were not captured by our survey, completion of a dermatology RF is not without disadvantages. Fellowships often are unfunded and offered in cities with high costs of living. Additionally, students are forced to delay graduation from medical school by a year at minimum and continue to accrue interest on medical school loans during this time. The financial burdens of completing an RF may exclude students of lower socioeconomic status and contribute to a decrease in diversity within the field. Dermatology has been found to be the second least diverse specialty, behind orthopedics.⁶ Soliman et al⁷ found that racial minorities and low-income students were more likely to cite socioeconomic barriers as factors involved in their decision not to pursue a career in dermatology. This notion was supported by Rinderknecht et al,⁸ who found that Black and Latinx dermatology applicants were more likely to come from disadvantaged backgrounds, and Black applicants were more likely to indicate financial concerns as their primary reason for not pursuing an RF. The impact of accumulated student debt and decreased access should be carefully weighed against the potential benefits of an RF. However, as the USMLE transitions their Step 1 score reporting from numerical to a pass/fail system, it also is possible that dermatology programs will place more emphasis on research productivity when evaluating applications for residency. Overall, the decision to recommend an RF represents an extremely complex topic, as indicated by the results of this study.

Limitations—Our survey-based study is limited by response rate and response bias. Despite the large number of responses, the overall response rate cannot be determined because it is unknown how many total faculty members actually received the survey. Moreover, data collected from current dermatology residents who have completed RFs vs those who have not as they pertain to resident performance and preparedness for the rigors of a dermatology residency would be useful.

Dermatology residency positions continue to be highly coveted among applicants in the match. In 2019, dermatology proved to be the most competitive specialty, with 36.3% of US medical school seniors and independent applicants going unmatched.¹ Prior to the transition to a pass/fail system, the mean US Medical Licensing Examination (USMLE) Step 1 score for matched applicants increased from 247 in 2014 to 251 in 2019. The growing number of scholarly activities reported by applicants has contributed to the competitiveness of the specialty. In 2018, the mean number of abstracts, presentations, and publications reported by matched applicants was 14.71, which was higher than other competitive specialties, including orthopedic surgery and otolaryngology (11.5 and 10.4, respectively). Dermatology applicants who did not match in 2018 reported a mean of 8.6 abstracts, presentations, and publications, which was on par with successful applicants in many other specialties.¹ In 2011, Stratman and Ness² found that publishing manuscripts and listing research experience were factors strongly associated with matching into dermatology for reapplicants. These trends in reported research have added pressure for applicants to increase their publications.

Given that many students do not choose a career in dermatology until later in medical school, some students choose to take a gap year between their third and fourth years of medical school to pursue a research fellowship (RF) and produce publications, in theory to increase the chances of matching in dermatology. A survey of dermatology applicants conducted by Costello et al³ in 2021 found that, of the students who completed a gap year (n=90; 31.25%), 78.7% (n=71) of them completed an RF, and those who completed RFs were more likely to match at top dermatology residency programs (P<.01). The authors also reported that there was no significant difference in overall match rates between gap-year and non–gap-year applicants.³ Another survey of 328 medical students found that the most common reason students take years off for research during medical school is to increase competitiveness for residency application.⁴ Although it is clear that students completing an RF often find success in the match, there are limited published data on how those involved in selecting dermatology residents view this additional year. We surveyed faculty members participating in the resident selection process to assess their viewpoints on how RFs factored into an applicant’s odds of matching into dermatology residency and performance as a resident.

Materials and Methods

An institutional review board application was submitted through the Geisinger Health System (Danville, Pennsylvania), and an exemption to complete the survey was granted. The survey consisted of 16 questions via REDCap electronic data capture and was sent to a listserve of dermatology program directors who were asked to distribute the survey to program chairs and faculty members within their department. Survey questions evaluated the participants’ involvement in medical student advising and the residency selection process. Questions relating to the respondents’ opinions were based on a 5-point Likert scale on level of agreement (1=strongly agree; 5=strongly disagree) or importance (1=a great deal; 5=not at all). All responses were collected anonymously. Data points were compiled and analyzed using REDCap. Statistical analysis via χ² tests were conducted when appropriate.

Results

The survey was sent to 142 individuals and distributed to faculty members within those departments between August 16, 2019, and September 24, 2019. The survey elicited a total of 110 respondents. Demographic information is shown in eTable 1. Of these respondents, 35.5% were program directors, 23.6% were program chairs, 3.6% were both program director and program chair, and 37.3% were core faculty members. Although respondents’ roles were varied, 96.4% indicated that they were involved in both advising medical students and in selecting residents.

None of the respondents indicated that they always recommend that students complete an RF, and only 4.5% indicated that they usually recommend it; 40% of respondents rarely or never recommend an RF, while 55.5% sometimes recommend it. Although there was a variety of responses to how frequently faculty members recommend an RF, almost all respondents (98.2%) agreed that the reason medical students pursued an RF prior to residency application was to increase the competitiveness of their residency application. However, 20% of respondents believed that students in this cohort were seeking to gain a deeper understanding of the specialty, and 27.3% thought that this cohort had genuine interest in research. Interestingly, despite the medical students’ intentions of choosing an RF, most respondents (67.3%) agreed or strongly agreed that the publications produced by fellows make an impact on the dermatologic scientific community.

Although some respondents indicated that completion of an RF positively impacts resident performance with regard to patient care, most indicated that the impact was a little (26.4%) or not at all (50%). Additionally, a minority of respondents (11.8%) believed that RFs positively impact resident performance on in-service and board examinations at least a moderate amount, with 62.7% indicating no positive impact at all. Only 12.7% of participants agreed or strongly agreed that completion of an RF led to increased applicant involvement in research throughout their career, and most (73.6%) believed there were downsides to completing an RF. Finally, only 20% agreed or strongly agreed that students who completed an RF were more dedicated to the field of dermatology (eTable 2).

Further evaluation of the data indicated that the perceived utility of RFs did not affect respondents’ recommendation on whether to pursue an RF or not. For example, of the 4.5% of respondents who indicated that they always or usually recommended RFs, only 1 respondent believed that students who completed an RF were more dedicated to the field of dermatology than those who did not. Although 55.5% of respondents answered that they sometimes recommended completion of an RF, less than a quarter of this group believed that students who completed an RF were more likely to be heavily involved in research throughout their career (P=.99).

Overall, 11.8% of respondents indicated that completion of a dermatology RF influenced the evaluation of an applicant a great deal or a lot, while 53.6% of respondents indicated a little or no influence at all. Most respondents (62.8%) agreed or strongly agreed that completion of an RF can compensate for flaws in a residency application. Furthermore, when asked if completion of an RF could set 2 otherwise equivocal applicants apart from one another, 46.4% of respondents agreed or strongly agreed with the statement, while only 17.3% disagreed or strongly disagreed (eTable 2).

Comment

This study characterized how completion of an RF is viewed by those involved in advising medical students and selecting dermatology residents. The growing pressure for applicants to increase the number of publications combined with the competitiveness of applying for a dermatology residency position has led to increased participation in RFs. However, studies have found that students who completed an RF often did so despite a lack of interest.⁴ Nonetheless, little is known about how this is perceived by those involved in choosing residents.

We found that few respondents always or usually advised applicants to complete an RF, but the majority sometimes recommended them, demonstrating the complexity of this issue. Completion of an RF impacted 11.8% of respondents’ overall opinion of an applicant a lot or a great deal, while most respondents (53.6%) were influenced a little or not at all. However, 46.4% of respondents indicated that completion of a dermatology RF would set apart 2 applicants of otherwise equal standing, and 62.8% agreed or strongly agreed that completion of an RF would compensate for flaws in an application. These responses align with the findings of a study conducted by Kaffenberger et al,⁵ who surveyed members of the Association of Professors of Dermatology and found that 74.5% (73/98) of mentors almost always or sometimes recommended a research gap year for reasons that included low grades, low USMLE Step scores, and little research. These data suggest that completion of an RF can give a competitive advantage to applicants despite most advisors acknowledging that these applicants are not likely to be involved in research throughout their careers, perform better on standardized examinations, or provide better patient care.

Given the complexity of this issue, respondents may not have been able to accurately answer the question about how much an RF influenced their overall opinion of an applicant because of subconscious bias. Furthermore, respondents likely tailored their recommendations to complete an RF based on individual applicant strengths and weaknesses, and the specific reasons why one may recommend an RF need to be further investigated.

Although there may be other perceived advantages to RFs that were not captured by our survey, completion of a dermatology RF is not without disadvantages. Fellowships often are unfunded and offered in cities with high costs of living. Additionally, students are forced to delay graduation from medical school by a year at minimum and continue to accrue interest on medical school loans during this time. The financial burdens of completing an RF may exclude students of lower socioeconomic status and contribute to a decrease in diversity within the field. Dermatology has been found to be the second least diverse specialty, behind orthopedics.⁶ Soliman et al⁷ found that racial minorities and low-income students were more likely to cite socioeconomic barriers as factors involved in their decision not to pursue a career in dermatology. This notion was supported by Rinderknecht et al,⁸ who found that Black and Latinx dermatology applicants were more likely to come from disadvantaged backgrounds, and Black applicants were more likely to indicate financial concerns as their primary reason for not pursuing an RF. The impact of accumulated student debt and decreased access should be carefully weighed against the potential benefits of an RF. However, as the USMLE transitions their Step 1 score reporting from numerical to a pass/fail system, it also is possible that dermatology programs will place more emphasis on research productivity when evaluating applications for residency. Overall, the decision to recommend an RF represents an extremely complex topic, as indicated by the results of this study.

Limitations—Our survey-based study is limited by response rate and response bias. Despite the large number of responses, the overall response rate cannot be determined because it is unknown how many total faculty members actually received the survey. Moreover, data collected from current dermatology residents who have completed RFs vs those who have not as they pertain to resident performance and preparedness for the rigors of a dermatology residency would be useful.

Melasma is a complex, long-lasting, acquired dermatologic pigmentation disorder resulting in grey-brown patches that last for more than 3 months. Sun-exposed areas including the nose, cheeks, forehead, and forearms are most likely to be affected.¹ In Southeast Asia, 0.25% to 4% of the population affected by melasma is aged 30 to 40 years.² In particular, melasma is a concern among pregnant women due to increased levels of melanocyte-stimulating hormones (MSHs) and is impacted by genetics, hormonal influence, and exposure to UV light.^3,4 In Pakistan, approximately 46% of women are affected by melasma during pregnancy.^2,5 Although few studies have focused on the clinical approaches to melasma in darker skin types, it continues to disproportionately affect the skin of color population.⁴

The areas of hyperpigmentation seen in melasma exhibit increased deposition of melanin in the epidermis and dermis, but melanocytes are not elevated. However, in areas of hyperpigmentation, the melanocytes are larger and more dendritic and demonstrate an increased level of melanogenesis.⁶ During pregnancy, especially in the third trimester, elevated levels of estrogen, progesterone, and MSH often are found in association with melasma.⁷ Tyrosinase (TYR) activity increases and cellular proliferation is reduced after treatment of melanocytes in culture with β-estradiol.⁸ Sex steroids increase transcription of genes encoding melanogenic enzymes in normal human melanocytes, especially TYR.⁹ These results are consistent with the notable increases in melanin synthesis and TYR activity reported for normal human melanocytes under similar conditions in culture.¹⁰ Because melanocytes contain both cytosolic and nuclear estrogen receptors, melanocytes in patients with melasma may be inherently more sensitive to the stimulatory effects of estrogens and possibly other steroid hormones.¹¹

The current treatment options for melasma have varying levels of success and include topical depigmenting agents such as hydroquinone, tretinoin, azelaic acid, kojic acid, and corticosteroids; dermabrasion; and chemical peels.^12-14 Chemical peels with glycolic acid, salicylic acid, lactic acid, trichloroacetic acid, and phenol, as well as laser therapy, are reliable management options.^13,14 Traditionally, melasma has been treated with a combination of modalities along with photoprotection and trigger avoidance.¹²

The efficacy and safety of the available therapies for melasma are still controversial and require further exploration. In recent years, off-label tranexamic acid (TA) has emerged as a potential therapy for melasma. Although the mechanism of action remains unclear, TA may inhibit melanin synthesis by blocking the interaction between melanocytes and keratinocytes.¹⁵ Tranexamic acid also may reverse the abnormal dermal changes associated with melasma by inhibiting melanogenesis and angiogenesis.¹⁶

Although various therapeutic options exist for melasma, the search for a reliable option in patients with darker skin types continues.¹³ We sought to evaluate the efficacy of TA solution 5% in reducing the severity of melasma in South Asian patients, thereby improving patient outcomes and maximizing patient satisfaction. Topical TA is inexpensive and readily accessible and does not cause systemic side effects. These qualities make it a promising treatment compared to traditional therapies.

Methods

We conducted a randomized controlled trial at Rawalpindi Medical Institute (Punjab, Pakistan). The researchers obtained informed consent for all enrolled patients. Cases were sampled from the original patient population seen at the office using nonprobability consecutive sampling. The sample size was calculated with a 95% CI, margin of error of 9%, and expected percentage of efficacy of 86.1% by using TA solution 5%. South Asian male and female patients aged 20 to 45 years with melasma were included in the analysis. Patients were excluded if they were already taking TA, oral contraceptive pills, or photosensitizing drugs (eg, nonsteroidal anti-inflammatory drugs, tetracyclines, phenytoin, carbamazepine); were pregnant; had chronic kidney disease (creatinine >2.0 mg/dL); had cardiac abnormalities (abnormal electrocardiogram); had hematologic disorders (international normalized ratio >2); or had received another melasma treatment within the last 3 to 6 months.

All enrolled patients underwent a detailed history and physical examination. Patient demographics were subsequently noted, including age, sex, history of diabetes mellitus or hypertension, and duration of melasma. The melasma area and severity index (MASI) score of each patient was calculated at baseline, and a corresponding photograph was taken.

The topical solution was prepared with 5 g of TA dissolved in 10 cc of ethanol at 96 °F, 10 cc of 1,3-butanediol, and distilled water up to 100 cc. The TA solution was applied to the affected areas once daily by the patient for 12 weeks. Each application covered the affected areas completely. Patients were instructed to apply sunscreen with sun protection factor 60 to those same areas for UV protection after 15 minutes of TA application. Biweekly follow-ups were scheduled during the trial, and the MASI score was recorded at these visits. If the mean MASI score was reduced by half after 12 weeks of treatment, then the treatment was considered efficacious with a 95% CI.

The percentage reduction from baseline was calculated as follows: percentage reduction=(baseline score– follow-up score)/baseline score×100.

Statistical Analysis—Data were analyzed in SPSS Statistics 25 (IBM). The quantitative variables of age, duration of melasma, and body mass index were presented as mean (SD). Qualitative variables such as sex, history of diabetes mellitus or hypertension, site of melasma, and efficacy were presented as frequencies and percentages. Mean MASI scores at baseline and 12 weeks posttreatment were compared using a paired t test (P≤.05). Data were stratified for age, sex, history of diabetes mellitus or hypertension, site of melasma, and duration of melasma, and a χ² test was applied to compare efficacy in stratified groups (P≤.05).

Results

Sixty patients were enrolled in the study. Of them, 17 (28.33%) were male, and 43 (71.67%) were female (2:5 ratio). They ranged in age from 20 to 45 years (mean [SD], 31.93 [6.26] years). Thirty-seven patients (61.67%) were aged 31 to 45 years of age (Table 1). The mean (SD) duration of disease was 10.18 (2.10) months. The response to TA was recorded based on patient distribution according to the site of melasma as well as history of diabetes mellitus and hypertension.

Topical TA was found to be efficacious for melasma in 50 (83.33%) patients. The mean (SD) baseline and week 12 MASI scores were 23.15 (5.02) and 12.71 (4.10)(P<.0001), respectively (Table 2). The stratification of efficacy with respect to age, sex, duration of melasma, site of melasma, and history of diabetes mellitus or hypertension is shown in the eTable. The site of melasma was significant with respect to stratification of efficacy. On the forehead, TA was found to be efficacious in 11 patients and nonefficacious in 0 patients (P=.036). In the malar region, it was efficacious in 16 patients and nonefficacious in 1 patient (P=.036). Finally, on the chin, it was efficacious in 23 patients and nonefficacious in 9 patients (P=.036).

Comment

Melasma Presentation and Development—Melasma is a chronic skin condition that more often affects patients with darker skin types. This condition is characterized by hyperpigmentation of skin that is directly exposed to the sun, such as the cheek, nose, forehead, and above the upper lip.¹⁷ Although the mechanism behind how melasma develops is unknown, one theory suggests that UV light can lead to increased plasmin in keratinocytes.¹⁸ This increased plasmin will thereby increase the arachidonic acid and α-MSH, leading to the observed uneven hyperpigmentation that is notable in melasma. Melasma is common in patients using oral contraceptives or expired cosmetic drugs; in those who are pregnant; and in those with liver dysfunction.¹⁸ Melasma has a negative impact on patients’ quality of life because of substantial psychological and social distress. Thus, finding an accessible treatment is imperative.¹⁹

Melasma Management—The most common treatments for melasma have been topical bleaching agents and photoprotection. Combination therapy options include chemical peels, dermabrasion, and laser treatments, though they present with limited efficacy.^17,20 Because melasma focuses on pigmentation correction, topical treatments work to disturb melanocyte pigment production at the enzymatic level.²¹ Tyrosinase is rate limiting in melanin production, as it converts L-tyrosinase to L-3,4-dihydroxyphenylalanine, using copper to interact with L-3,4-dihydroxyphenylalanine as a cofactor in the active site.²² Therefore, tyrosine is a major target for many drugs that have been developed for melasma to decrease melaninization.²¹

Recently, research has focused on the effects of topical, intradermal, and oral TA for melasma.¹⁷ Tranexamic acid most commonly has been used in medicine as a fibrinolytic agent because of its antiplasmin properties. It has been hypothesized that TA can inhibit the release of paracrine melanogenic factors that normally act to stimulate melanocytes.¹⁷ Although studies have supported the safety and efficacy of TA, there remains a lack of clinical studies that are sufficiently powered. No definitive consensus on the use of TA for melasma currently exists, which indicates the need for large-scale, randomized, controlled trials.²³

One trial (N=25) found that TA solution 5% achieved efficacy (>50% reduction in MASI score from baseline) in 86.1% of patients with melasma.²⁴ In another study (N=18), topical TA 5% achieved efficacy (>50% reduction in MASI score) in 86% of patients with melasma.²⁵

Melasma Comorbidities—To determine if certain comorbidities, such as diabetes mellitus or hypertension, influenced the progression of melasma, we stratified the efficacy results for patients with these 2 comorbidities, which showed no significant difference (P=.794 and P=.101, respectively). Thus, the relatively higher prevalence of diabetes mellitus (16 patients) and hypertension (11 patients) did not contribute to the efficacy of TA in lowering MASI scores over the 12-week period, which supports the findings of Doolan and Gupta,²⁶ who investigated the endocrinologic conditions associated with melasma and found no such association with diabetes mellitus or hypertension.

TA Formulations for Melasma—The efficacy of topical TA has been explored in several studies. Six studies with sample sizes of 13 to 50 patients each showed statistically significant differences in MASI scores between baseline and following TA treatment (P<.001).^27-32 Several formulations and regimens were utilized, including TA cream 3% for 12 weeks, TA gel 5% for 12 weeks, TA solution 3% for 12 weeks, TA liposome 5% for 12 weeks, and TA solution 2% for 12 weeks.¹⁸ Additionally, these studies found TA to be effective in limiting dyschromia and decreasing MASI scores. There were no statistically significant differences between formulations and method of application. Topical TA has been found to be just as effective as other treatments for melasma, including intradermal TA injections, topical hydroquinone, and a combination of topical hydroquinone and dexamethasone.¹⁸

Further study of the efficacy of intradermal TA is necessary because many human trials have lacked statistical significance or a control group. Lee et al³² conducted a trial of 100 female patients who received weekly intradermal TA microinjections for 12 weeks. After 8 and 12 weeks, MASI scores decreased significantly (P<.01).³² Similarly, Badran et al³³ observed 60 female patients in 3 trial groups: group A received TA (4 mg/mL) intradermal injections every 2 weeks, group B received TA (10 mg/mL) intradermal injections every 2 weeks, and group C received TA cream 10% twice daily. Although all groups showed improvement in MASI, group B, which had the highest intradermal TA concentration, exhibited the most improvement. Thus, it was determined that intradermal application led to better results, but the cream was still effective.³³

Saki et al³⁴ conducted a randomized, split-face trial of 37 patients comparing the efficacy of intradermal TA and topical hydroquinone. Each group was treated with either monthly intradermal TA injections or nightly hydroquinone for 3 months. After 4 weeks of treatment, TA initially had a greater improvement. However, after 20 weeks, the overall changes were not significant between the 2 groups.³⁴ Pazyar et al³⁵ conducted a randomized, split-face trial of 49 patients comparing the efficacy of intradermal TA and hydroquinone cream. After 24 weeks of biweekly TA injections or twice-daily hydroquinone, there were no statistically significant differences in the decreased MASI scores between treatments.³⁵ Additional large, double-blind, controlled trials are needed to thoroughly assess the role of intradermal TA in comparison to its treatment counterpart of hydroquinone.

Ebrahimi and Naeini²⁹ conducted a 12-week, double-blind, split-phase trial of 50 Iranian melasma patients, which showed that 27.3% of patients rated the improvement in melasma as excellent, 42.4% as good, and 30.3% as fair after using TA solution 3%. Wu et al³⁶ also showed a total melasma improvement rate of 80.9% in 256 patients with long-term oral use of TA. In a study by Kim et al³¹ (N=245), the mean MASI score considerably decreased after topical TA use, with a total response rate of 95.6%. In another study, Atefi et al³⁷ presented significantly increased levels of satisfaction in patients treated with topical TA 5% vs hydroquinone (P=.015).

Melasma in Patients With Darker Skin Types—Special attention must be given to choosing the appropriate medication in melasma patients with darker skin types, as there is an increased risk for postinflammatory hyperpigmentation. Currently, few randomized controlled trials exist that fulfill the criteria of evaluating pharmacologic options for patients with melasma, and even fewer studies solely focus on patients with darker skin types.³⁸ In addition to treatment advances, patients must be educated on the need to avoid sun exposure when possible or to use photoprotection, especially in the South Asian region, where these practices rarely are taught. Our study provided a unique analysis regarding the efficacy of TA solution 5% for the treatment of melasma in patients of South Asian descent. Clinicians can use these findings as a foundation for treating all patients with melasma but particularly those with darker skin types.

Study Limitations—Our study consisted of 60 patients; although our study had more patients than similar trials, larger studies are needed. Additionally, other variables were excluded from our analysis, such as comorbidities beyond diabetes mellitus and hypertension.

Conclusion

This study contributes to the growing field of melasma therapeutics by evaluating the efficacy of using TA solution 5% for the treatment of melasma in South Asian patients with darker skin types. Clinicians may use our study to broaden their treatment options for a common condition while also addressing the lack of clinical options for patients with darker skin types. Further studies investigating the effectiveness of TA in large clinical trials in humans are warranted to understand the efficacy and the risk for any complications.

Melasma is a complex, long-lasting, acquired dermatologic pigmentation disorder resulting in grey-brown patches that last for more than 3 months. Sun-exposed areas including the nose, cheeks, forehead, and forearms are most likely to be affected.¹ In Southeast Asia, 0.25% to 4% of the population affected by melasma is aged 30 to 40 years.² In particular, melasma is a concern among pregnant women due to increased levels of melanocyte-stimulating hormones (MSHs) and is impacted by genetics, hormonal influence, and exposure to UV light.^3,4 In Pakistan, approximately 46% of women are affected by melasma during pregnancy.^2,5 Although few studies have focused on the clinical approaches to melasma in darker skin types, it continues to disproportionately affect the skin of color population.⁴

The areas of hyperpigmentation seen in melasma exhibit increased deposition of melanin in the epidermis and dermis, but melanocytes are not elevated. However, in areas of hyperpigmentation, the melanocytes are larger and more dendritic and demonstrate an increased level of melanogenesis.⁶ During pregnancy, especially in the third trimester, elevated levels of estrogen, progesterone, and MSH often are found in association with melasma.⁷ Tyrosinase (TYR) activity increases and cellular proliferation is reduced after treatment of melanocytes in culture with β-estradiol.⁸ Sex steroids increase transcription of genes encoding melanogenic enzymes in normal human melanocytes, especially TYR.⁹ These results are consistent with the notable increases in melanin synthesis and TYR activity reported for normal human melanocytes under similar conditions in culture.¹⁰ Because melanocytes contain both cytosolic and nuclear estrogen receptors, melanocytes in patients with melasma may be inherently more sensitive to the stimulatory effects of estrogens and possibly other steroid hormones.¹¹

The current treatment options for melasma have varying levels of success and include topical depigmenting agents such as hydroquinone, tretinoin, azelaic acid, kojic acid, and corticosteroids; dermabrasion; and chemical peels.^12-14 Chemical peels with glycolic acid, salicylic acid, lactic acid, trichloroacetic acid, and phenol, as well as laser therapy, are reliable management options.^13,14 Traditionally, melasma has been treated with a combination of modalities along with photoprotection and trigger avoidance.¹²

The efficacy and safety of the available therapies for melasma are still controversial and require further exploration. In recent years, off-label tranexamic acid (TA) has emerged as a potential therapy for melasma. Although the mechanism of action remains unclear, TA may inhibit melanin synthesis by blocking the interaction between melanocytes and keratinocytes.¹⁵ Tranexamic acid also may reverse the abnormal dermal changes associated with melasma by inhibiting melanogenesis and angiogenesis.¹⁶

Although various therapeutic options exist for melasma, the search for a reliable option in patients with darker skin types continues.¹³ We sought to evaluate the efficacy of TA solution 5% in reducing the severity of melasma in South Asian patients, thereby improving patient outcomes and maximizing patient satisfaction. Topical TA is inexpensive and readily accessible and does not cause systemic side effects. These qualities make it a promising treatment compared to traditional therapies.

Methods

We conducted a randomized controlled trial at Rawalpindi Medical Institute (Punjab, Pakistan). The researchers obtained informed consent for all enrolled patients. Cases were sampled from the original patient population seen at the office using nonprobability consecutive sampling. The sample size was calculated with a 95% CI, margin of error of 9%, and expected percentage of efficacy of 86.1% by using TA solution 5%. South Asian male and female patients aged 20 to 45 years with melasma were included in the analysis. Patients were excluded if they were already taking TA, oral contraceptive pills, or photosensitizing drugs (eg, nonsteroidal anti-inflammatory drugs, tetracyclines, phenytoin, carbamazepine); were pregnant; had chronic kidney disease (creatinine >2.0 mg/dL); had cardiac abnormalities (abnormal electrocardiogram); had hematologic disorders (international normalized ratio >2); or had received another melasma treatment within the last 3 to 6 months.

All enrolled patients underwent a detailed history and physical examination. Patient demographics were subsequently noted, including age, sex, history of diabetes mellitus or hypertension, and duration of melasma. The melasma area and severity index (MASI) score of each patient was calculated at baseline, and a corresponding photograph was taken.

The topical solution was prepared with 5 g of TA dissolved in 10 cc of ethanol at 96 °F, 10 cc of 1,3-butanediol, and distilled water up to 100 cc. The TA solution was applied to the affected areas once daily by the patient for 12 weeks. Each application covered the affected areas completely. Patients were instructed to apply sunscreen with sun protection factor 60 to those same areas for UV protection after 15 minutes of TA application. Biweekly follow-ups were scheduled during the trial, and the MASI score was recorded at these visits. If the mean MASI score was reduced by half after 12 weeks of treatment, then the treatment was considered efficacious with a 95% CI.

The percentage reduction from baseline was calculated as follows: percentage reduction=(baseline score– follow-up score)/baseline score×100.

Statistical Analysis—Data were analyzed in SPSS Statistics 25 (IBM). The quantitative variables of age, duration of melasma, and body mass index were presented as mean (SD). Qualitative variables such as sex, history of diabetes mellitus or hypertension, site of melasma, and efficacy were presented as frequencies and percentages. Mean MASI scores at baseline and 12 weeks posttreatment were compared using a paired t test (P≤.05). Data were stratified for age, sex, history of diabetes mellitus or hypertension, site of melasma, and duration of melasma, and a χ² test was applied to compare efficacy in stratified groups (P≤.05).

Results

Sixty patients were enrolled in the study. Of them, 17 (28.33%) were male, and 43 (71.67%) were female (2:5 ratio). They ranged in age from 20 to 45 years (mean [SD], 31.93 [6.26] years). Thirty-seven patients (61.67%) were aged 31 to 45 years of age (Table 1). The mean (SD) duration of disease was 10.18 (2.10) months. The response to TA was recorded based on patient distribution according to the site of melasma as well as history of diabetes mellitus and hypertension.

Topical TA was found to be efficacious for melasma in 50 (83.33%) patients. The mean (SD) baseline and week 12 MASI scores were 23.15 (5.02) and 12.71 (4.10)(P<.0001), respectively (Table 2). The stratification of efficacy with respect to age, sex, duration of melasma, site of melasma, and history of diabetes mellitus or hypertension is shown in the eTable. The site of melasma was significant with respect to stratification of efficacy. On the forehead, TA was found to be efficacious in 11 patients and nonefficacious in 0 patients (P=.036). In the malar region, it was efficacious in 16 patients and nonefficacious in 1 patient (P=.036). Finally, on the chin, it was efficacious in 23 patients and nonefficacious in 9 patients (P=.036).

Comment

Melasma Presentation and Development—Melasma is a chronic skin condition that more often affects patients with darker skin types. This condition is characterized by hyperpigmentation of skin that is directly exposed to the sun, such as the cheek, nose, forehead, and above the upper lip.¹⁷ Although the mechanism behind how melasma develops is unknown, one theory suggests that UV light can lead to increased plasmin in keratinocytes.¹⁸ This increased plasmin will thereby increase the arachidonic acid and α-MSH, leading to the observed uneven hyperpigmentation that is notable in melasma. Melasma is common in patients using oral contraceptives or expired cosmetic drugs; in those who are pregnant; and in those with liver dysfunction.¹⁸ Melasma has a negative impact on patients’ quality of life because of substantial psychological and social distress. Thus, finding an accessible treatment is imperative.¹⁹

Melasma Management—The most common treatments for melasma have been topical bleaching agents and photoprotection. Combination therapy options include chemical peels, dermabrasion, and laser treatments, though they present with limited efficacy.^17,20 Because melasma focuses on pigmentation correction, topical treatments work to disturb melanocyte pigment production at the enzymatic level.²¹ Tyrosinase is rate limiting in melanin production, as it converts L-tyrosinase to L-3,4-dihydroxyphenylalanine, using copper to interact with L-3,4-dihydroxyphenylalanine as a cofactor in the active site.²² Therefore, tyrosine is a major target for many drugs that have been developed for melasma to decrease melaninization.²¹

Recently, research has focused on the effects of topical, intradermal, and oral TA for melasma.¹⁷ Tranexamic acid most commonly has been used in medicine as a fibrinolytic agent because of its antiplasmin properties. It has been hypothesized that TA can inhibit the release of paracrine melanogenic factors that normally act to stimulate melanocytes.¹⁷ Although studies have supported the safety and efficacy of TA, there remains a lack of clinical studies that are sufficiently powered. No definitive consensus on the use of TA for melasma currently exists, which indicates the need for large-scale, randomized, controlled trials.²³

One trial (N=25) found that TA solution 5% achieved efficacy (>50% reduction in MASI score from baseline) in 86.1% of patients with melasma.²⁴ In another study (N=18), topical TA 5% achieved efficacy (>50% reduction in MASI score) in 86% of patients with melasma.²⁵

Melasma Comorbidities—To determine if certain comorbidities, such as diabetes mellitus or hypertension, influenced the progression of melasma, we stratified the efficacy results for patients with these 2 comorbidities, which showed no significant difference (P=.794 and P=.101, respectively). Thus, the relatively higher prevalence of diabetes mellitus (16 patients) and hypertension (11 patients) did not contribute to the efficacy of TA in lowering MASI scores over the 12-week period, which supports the findings of Doolan and Gupta,²⁶ who investigated the endocrinologic conditions associated with melasma and found no such association with diabetes mellitus or hypertension.

TA Formulations for Melasma—The efficacy of topical TA has been explored in several studies. Six studies with sample sizes of 13 to 50 patients each showed statistically significant differences in MASI scores between baseline and following TA treatment (P<.001).^27-32 Several formulations and regimens were utilized, including TA cream 3% for 12 weeks, TA gel 5% for 12 weeks, TA solution 3% for 12 weeks, TA liposome 5% for 12 weeks, and TA solution 2% for 12 weeks.¹⁸ Additionally, these studies found TA to be effective in limiting dyschromia and decreasing MASI scores. There were no statistically significant differences between formulations and method of application. Topical TA has been found to be just as effective as other treatments for melasma, including intradermal TA injections, topical hydroquinone, and a combination of topical hydroquinone and dexamethasone.¹⁸

Further study of the efficacy of intradermal TA is necessary because many human trials have lacked statistical significance or a control group. Lee et al³² conducted a trial of 100 female patients who received weekly intradermal TA microinjections for 12 weeks. After 8 and 12 weeks, MASI scores decreased significantly (P<.01).³² Similarly, Badran et al³³ observed 60 female patients in 3 trial groups: group A received TA (4 mg/mL) intradermal injections every 2 weeks, group B received TA (10 mg/mL) intradermal injections every 2 weeks, and group C received TA cream 10% twice daily. Although all groups showed improvement in MASI, group B, which had the highest intradermal TA concentration, exhibited the most improvement. Thus, it was determined that intradermal application led to better results, but the cream was still effective.³³

Saki et al³⁴ conducted a randomized, split-face trial of 37 patients comparing the efficacy of intradermal TA and topical hydroquinone. Each group was treated with either monthly intradermal TA injections or nightly hydroquinone for 3 months. After 4 weeks of treatment, TA initially had a greater improvement. However, after 20 weeks, the overall changes were not significant between the 2 groups.³⁴ Pazyar et al³⁵ conducted a randomized, split-face trial of 49 patients comparing the efficacy of intradermal TA and hydroquinone cream. After 24 weeks of biweekly TA injections or twice-daily hydroquinone, there were no statistically significant differences in the decreased MASI scores between treatments.³⁵ Additional large, double-blind, controlled trials are needed to thoroughly assess the role of intradermal TA in comparison to its treatment counterpart of hydroquinone.

Ebrahimi and Naeini²⁹ conducted a 12-week, double-blind, split-phase trial of 50 Iranian melasma patients, which showed that 27.3% of patients rated the improvement in melasma as excellent, 42.4% as good, and 30.3% as fair after using TA solution 3%. Wu et al³⁶ also showed a total melasma improvement rate of 80.9% in 256 patients with long-term oral use of TA. In a study by Kim et al³¹ (N=245), the mean MASI score considerably decreased after topical TA use, with a total response rate of 95.6%. In another study, Atefi et al³⁷ presented significantly increased levels of satisfaction in patients treated with topical TA 5% vs hydroquinone (P=.015).

Melasma in Patients With Darker Skin Types—Special attention must be given to choosing the appropriate medication in melasma patients with darker skin types, as there is an increased risk for postinflammatory hyperpigmentation. Currently, few randomized controlled trials exist that fulfill the criteria of evaluating pharmacologic options for patients with melasma, and even fewer studies solely focus on patients with darker skin types.³⁸ In addition to treatment advances, patients must be educated on the need to avoid sun exposure when possible or to use photoprotection, especially in the South Asian region, where these practices rarely are taught. Our study provided a unique analysis regarding the efficacy of TA solution 5% for the treatment of melasma in patients of South Asian descent. Clinicians can use these findings as a foundation for treating all patients with melasma but particularly those with darker skin types.

Study Limitations—Our study consisted of 60 patients; although our study had more patients than similar trials, larger studies are needed. Additionally, other variables were excluded from our analysis, such as comorbidities beyond diabetes mellitus and hypertension.

Conclusion

This study contributes to the growing field of melasma therapeutics by evaluating the efficacy of using TA solution 5% for the treatment of melasma in South Asian patients with darker skin types. Clinicians may use our study to broaden their treatment options for a common condition while also addressing the lack of clinical options for patients with darker skin types. Further studies investigating the effectiveness of TA in large clinical trials in humans are warranted to understand the efficacy and the risk for any complications.

Melasma is a complex, long-lasting, acquired dermatologic pigmentation disorder resulting in grey-brown patches that last for more than 3 months. Sun-exposed areas including the nose, cheeks, forehead, and forearms are most likely to be affected.¹ In Southeast Asia, 0.25% to 4% of the population affected by melasma is aged 30 to 40 years.² In particular, melasma is a concern among pregnant women due to increased levels of melanocyte-stimulating hormones (MSHs) and is impacted by genetics, hormonal influence, and exposure to UV light.^3,4 In Pakistan, approximately 46% of women are affected by melasma during pregnancy.^2,5 Although few studies have focused on the clinical approaches to melasma in darker skin types, it continues to disproportionately affect the skin of color population.⁴

The areas of hyperpigmentation seen in melasma exhibit increased deposition of melanin in the epidermis and dermis, but melanocytes are not elevated. However, in areas of hyperpigmentation, the melanocytes are larger and more dendritic and demonstrate an increased level of melanogenesis.⁶ During pregnancy, especially in the third trimester, elevated levels of estrogen, progesterone, and MSH often are found in association with melasma.⁷ Tyrosinase (TYR) activity increases and cellular proliferation is reduced after treatment of melanocytes in culture with β-estradiol.⁸ Sex steroids increase transcription of genes encoding melanogenic enzymes in normal human melanocytes, especially TYR.⁹ These results are consistent with the notable increases in melanin synthesis and TYR activity reported for normal human melanocytes under similar conditions in culture.¹⁰ Because melanocytes contain both cytosolic and nuclear estrogen receptors, melanocytes in patients with melasma may be inherently more sensitive to the stimulatory effects of estrogens and possibly other steroid hormones.¹¹

The current treatment options for melasma have varying levels of success and include topical depigmenting agents such as hydroquinone, tretinoin, azelaic acid, kojic acid, and corticosteroids; dermabrasion; and chemical peels.^12-14 Chemical peels with glycolic acid, salicylic acid, lactic acid, trichloroacetic acid, and phenol, as well as laser therapy, are reliable management options.^13,14 Traditionally, melasma has been treated with a combination of modalities along with photoprotection and trigger avoidance.¹²

The efficacy and safety of the available therapies for melasma are still controversial and require further exploration. In recent years, off-label tranexamic acid (TA) has emerged as a potential therapy for melasma. Although the mechanism of action remains unclear, TA may inhibit melanin synthesis by blocking the interaction between melanocytes and keratinocytes.¹⁵ Tranexamic acid also may reverse the abnormal dermal changes associated with melasma by inhibiting melanogenesis and angiogenesis.¹⁶

Although various therapeutic options exist for melasma, the search for a reliable option in patients with darker skin types continues.¹³ We sought to evaluate the efficacy of TA solution 5% in reducing the severity of melasma in South Asian patients, thereby improving patient outcomes and maximizing patient satisfaction. Topical TA is inexpensive and readily accessible and does not cause systemic side effects. These qualities make it a promising treatment compared to traditional therapies.

Methods

We conducted a randomized controlled trial at Rawalpindi Medical Institute (Punjab, Pakistan). The researchers obtained informed consent for all enrolled patients. Cases were sampled from the original patient population seen at the office using nonprobability consecutive sampling. The sample size was calculated with a 95% CI, margin of error of 9%, and expected percentage of efficacy of 86.1% by using TA solution 5%. South Asian male and female patients aged 20 to 45 years with melasma were included in the analysis. Patients were excluded if they were already taking TA, oral contraceptive pills, or photosensitizing drugs (eg, nonsteroidal anti-inflammatory drugs, tetracyclines, phenytoin, carbamazepine); were pregnant; had chronic kidney disease (creatinine >2.0 mg/dL); had cardiac abnormalities (abnormal electrocardiogram); had hematologic disorders (international normalized ratio >2); or had received another melasma treatment within the last 3 to 6 months.

All enrolled patients underwent a detailed history and physical examination. Patient demographics were subsequently noted, including age, sex, history of diabetes mellitus or hypertension, and duration of melasma. The melasma area and severity index (MASI) score of each patient was calculated at baseline, and a corresponding photograph was taken.

The topical solution was prepared with 5 g of TA dissolved in 10 cc of ethanol at 96 °F, 10 cc of 1,3-butanediol, and distilled water up to 100 cc. The TA solution was applied to the affected areas once daily by the patient for 12 weeks. Each application covered the affected areas completely. Patients were instructed to apply sunscreen with sun protection factor 60 to those same areas for UV protection after 15 minutes of TA application. Biweekly follow-ups were scheduled during the trial, and the MASI score was recorded at these visits. If the mean MASI score was reduced by half after 12 weeks of treatment, then the treatment was considered efficacious with a 95% CI.

The percentage reduction from baseline was calculated as follows: percentage reduction=(baseline score– follow-up score)/baseline score×100.

Statistical Analysis—Data were analyzed in SPSS Statistics 25 (IBM). The quantitative variables of age, duration of melasma, and body mass index were presented as mean (SD). Qualitative variables such as sex, history of diabetes mellitus or hypertension, site of melasma, and efficacy were presented as frequencies and percentages. Mean MASI scores at baseline and 12 weeks posttreatment were compared using a paired t test (P≤.05). Data were stratified for age, sex, history of diabetes mellitus or hypertension, site of melasma, and duration of melasma, and a χ² test was applied to compare efficacy in stratified groups (P≤.05).

Results

Sixty patients were enrolled in the study. Of them, 17 (28.33%) were male, and 43 (71.67%) were female (2:5 ratio). They ranged in age from 20 to 45 years (mean [SD], 31.93 [6.26] years). Thirty-seven patients (61.67%) were aged 31 to 45 years of age (Table 1). The mean (SD) duration of disease was 10.18 (2.10) months. The response to TA was recorded based on patient distribution according to the site of melasma as well as history of diabetes mellitus and hypertension.

Topical TA was found to be efficacious for melasma in 50 (83.33%) patients. The mean (SD) baseline and week 12 MASI scores were 23.15 (5.02) and 12.71 (4.10)(P<.0001), respectively (Table 2). The stratification of efficacy with respect to age, sex, duration of melasma, site of melasma, and history of diabetes mellitus or hypertension is shown in the eTable. The site of melasma was significant with respect to stratification of efficacy. On the forehead, TA was found to be efficacious in 11 patients and nonefficacious in 0 patients (P=.036). In the malar region, it was efficacious in 16 patients and nonefficacious in 1 patient (P=.036). Finally, on the chin, it was efficacious in 23 patients and nonefficacious in 9 patients (P=.036).

Comment

Melasma Presentation and Development—Melasma is a chronic skin condition that more often affects patients with darker skin types. This condition is characterized by hyperpigmentation of skin that is directly exposed to the sun, such as the cheek, nose, forehead, and above the upper lip.¹⁷ Although the mechanism behind how melasma develops is unknown, one theory suggests that UV light can lead to increased plasmin in keratinocytes.¹⁸ This increased plasmin will thereby increase the arachidonic acid and α-MSH, leading to the observed uneven hyperpigmentation that is notable in melasma. Melasma is common in patients using oral contraceptives or expired cosmetic drugs; in those who are pregnant; and in those with liver dysfunction.¹⁸ Melasma has a negative impact on patients’ quality of life because of substantial psychological and social distress. Thus, finding an accessible treatment is imperative.¹⁹

Melasma Management—The most common treatments for melasma have been topical bleaching agents and photoprotection. Combination therapy options include chemical peels, dermabrasion, and laser treatments, though they present with limited efficacy.^17,20 Because melasma focuses on pigmentation correction, topical treatments work to disturb melanocyte pigment production at the enzymatic level.²¹ Tyrosinase is rate limiting in melanin production, as it converts L-tyrosinase to L-3,4-dihydroxyphenylalanine, using copper to interact with L-3,4-dihydroxyphenylalanine as a cofactor in the active site.²² Therefore, tyrosine is a major target for many drugs that have been developed for melasma to decrease melaninization.²¹

Recently, research has focused on the effects of topical, intradermal, and oral TA for melasma.¹⁷ Tranexamic acid most commonly has been used in medicine as a fibrinolytic agent because of its antiplasmin properties. It has been hypothesized that TA can inhibit the release of paracrine melanogenic factors that normally act to stimulate melanocytes.¹⁷ Although studies have supported the safety and efficacy of TA, there remains a lack of clinical studies that are sufficiently powered. No definitive consensus on the use of TA for melasma currently exists, which indicates the need for large-scale, randomized, controlled trials.²³

One trial (N=25) found that TA solution 5% achieved efficacy (>50% reduction in MASI score from baseline) in 86.1% of patients with melasma.²⁴ In another study (N=18), topical TA 5% achieved efficacy (>50% reduction in MASI score) in 86% of patients with melasma.²⁵

Melasma Comorbidities—To determine if certain comorbidities, such as diabetes mellitus or hypertension, influenced the progression of melasma, we stratified the efficacy results for patients with these 2 comorbidities, which showed no significant difference (P=.794 and P=.101, respectively). Thus, the relatively higher prevalence of diabetes mellitus (16 patients) and hypertension (11 patients) did not contribute to the efficacy of TA in lowering MASI scores over the 12-week period, which supports the findings of Doolan and Gupta,²⁶ who investigated the endocrinologic conditions associated with melasma and found no such association with diabetes mellitus or hypertension.

TA Formulations for Melasma—The efficacy of topical TA has been explored in several studies. Six studies with sample sizes of 13 to 50 patients each showed statistically significant differences in MASI scores between baseline and following TA treatment (P<.001).^27-32 Several formulations and regimens were utilized, including TA cream 3% for 12 weeks, TA gel 5% for 12 weeks, TA solution 3% for 12 weeks, TA liposome 5% for 12 weeks, and TA solution 2% for 12 weeks.¹⁸ Additionally, these studies found TA to be effective in limiting dyschromia and decreasing MASI scores. There were no statistically significant differences between formulations and method of application. Topical TA has been found to be just as effective as other treatments for melasma, including intradermal TA injections, topical hydroquinone, and a combination of topical hydroquinone and dexamethasone.¹⁸

Further study of the efficacy of intradermal TA is necessary because many human trials have lacked statistical significance or a control group. Lee et al³² conducted a trial of 100 female patients who received weekly intradermal TA microinjections for 12 weeks. After 8 and 12 weeks, MASI scores decreased significantly (P<.01).³² Similarly, Badran et al³³ observed 60 female patients in 3 trial groups: group A received TA (4 mg/mL) intradermal injections every 2 weeks, group B received TA (10 mg/mL) intradermal injections every 2 weeks, and group C received TA cream 10% twice daily. Although all groups showed improvement in MASI, group B, which had the highest intradermal TA concentration, exhibited the most improvement. Thus, it was determined that intradermal application led to better results, but the cream was still effective.³³

Saki et al³⁴ conducted a randomized, split-face trial of 37 patients comparing the efficacy of intradermal TA and topical hydroquinone. Each group was treated with either monthly intradermal TA injections or nightly hydroquinone for 3 months. After 4 weeks of treatment, TA initially had a greater improvement. However, after 20 weeks, the overall changes were not significant between the 2 groups.³⁴ Pazyar et al³⁵ conducted a randomized, split-face trial of 49 patients comparing the efficacy of intradermal TA and hydroquinone cream. After 24 weeks of biweekly TA injections or twice-daily hydroquinone, there were no statistically significant differences in the decreased MASI scores between treatments.³⁵ Additional large, double-blind, controlled trials are needed to thoroughly assess the role of intradermal TA in comparison to its treatment counterpart of hydroquinone.

Ebrahimi and Naeini²⁹ conducted a 12-week, double-blind, split-phase trial of 50 Iranian melasma patients, which showed that 27.3% of patients rated the improvement in melasma as excellent, 42.4% as good, and 30.3% as fair after using TA solution 3%. Wu et al³⁶ also showed a total melasma improvement rate of 80.9% in 256 patients with long-term oral use of TA. In a study by Kim et al³¹ (N=245), the mean MASI score considerably decreased after topical TA use, with a total response rate of 95.6%. In another study, Atefi et al³⁷ presented significantly increased levels of satisfaction in patients treated with topical TA 5% vs hydroquinone (P=.015).

Melasma in Patients With Darker Skin Types—Special attention must be given to choosing the appropriate medication in melasma patients with darker skin types, as there is an increased risk for postinflammatory hyperpigmentation. Currently, few randomized controlled trials exist that fulfill the criteria of evaluating pharmacologic options for patients with melasma, and even fewer studies solely focus on patients with darker skin types.³⁸ In addition to treatment advances, patients must be educated on the need to avoid sun exposure when possible or to use photoprotection, especially in the South Asian region, where these practices rarely are taught. Our study provided a unique analysis regarding the efficacy of TA solution 5% for the treatment of melasma in patients of South Asian descent. Clinicians can use these findings as a foundation for treating all patients with melasma but particularly those with darker skin types.

Study Limitations—Our study consisted of 60 patients; although our study had more patients than similar trials, larger studies are needed. Additionally, other variables were excluded from our analysis, such as comorbidities beyond diabetes mellitus and hypertension.

Conclusion

This study contributes to the growing field of melasma therapeutics by evaluating the efficacy of using TA solution 5% for the treatment of melasma in South Asian patients with darker skin types. Clinicians may use our study to broaden their treatment options for a common condition while also addressing the lack of clinical options for patients with darker skin types. Further studies investigating the effectiveness of TA in large clinical trials in humans are warranted to understand the efficacy and the risk for any complications.

The Diagnosis: Eccrine Poroma

Histopathology demonstrated epidermal thickening, epidermal protrusions, a well-defined mass of tumor cells that extended from the epidermis down to the dermis, and luminal structures. Poroid cells and ovoid nuclei with basophilic cytoplasm also were evident (Figure 1). Dermoscopy showed papillomatous growth, milky-red areas, and dotted vessels (Figure 2). Reflectance confocal microscopy (RCM) at the spinous layer showed hyporefractile, dark, roundish lumina surrounded by keratinocytes (Figure 3). Based on the histologic, dermoscopic, and RCM findings, our patient was diagnosed with eccrine poroma.

Goldman et al¹ first described poroma in 1956. Poromas, which include eccrine poroma, are a group of benign cutaneous neoplasms arising from the terminal eccrine or apocrine sweat gland ducts.² Histologically, poroid cells appear as cuboidal keratinocytes with monomorphous ovoid nuclei and discrete nucleoli.³ They usually appear as nodules or plaques with colors varying from flesh colored to red, brown, or bluish, and they clinically mimic several benign and malignant skin tumors. The differential diagnosis may include keratoacanthoma, plantar wart, verrucous carcinoma, basal cell carcinoma, and squamous cell carcinoma. Poromas can be of eccrine or apocrine origin.⁴ They also belong to a broad group of neoplasms, including nodular hidradenomas, clear cell hidradenomas, hidroacanthoma simplex, dermal duct tumors, and hidradenomas.⁵ Four subtypes—poroma, poroid hidradenoma, hidroacanthoma simplex, and dermal duct tumor—have been documented.⁶ Because poromas have nonspecific and variable clinical presentations, they often are misdiagnosed as other skin neoplasms, and differentiation may be difficult. For example, some cases of poroma present with follicular, sebaceous, and/or apocrine differentiation, leading to difficulty in diagnosis.

Characteristic features of eccrine poroma seen on dermoscopy and RCM have the potential to aid in the diagnosis compared to histopathology. Marchetti et al⁷ proposed 4 patterns of characteristic dermoscopic findings. Pattern 1 refers to the classic description with bleeding spots, a structureless yellow appearance, milkyred globules, and branched vessels. Patterns 2 and 3 simulate basal cell carcinoma, dermal nevus, or vascular tumors. Pattern 4 refers to tumors that are large in size and resemble keratinizing neoplasms.⁷ Brugués et al⁸ described poromas with the following RCM findings: an atypical honeycomb shape that was well separated from the normal epithelium, hyporefractile nests with atypical cells, lack of palisading, and dark holes. One study described RCM parameters as cords without palisading, dark holes, prominent vascularization, and abundant stroma—findings that were positively associated with poroma in a univariate analysis. These findings assist in distinguishing poromas from other conditions in the differential diagnosis.⁹

There is a substantial overlap in clinical appearance with malignant conditions, including basal cell carcinoma, squamous cell carcinoma, cutaneous metastases, and Paget disease; therefore, the use of dermoscopy and RCM may be helpful in the diagnosis and recognition of specific features, as well as the corresponding patterns of poroma. Poromas commonly display vascularized features due to the variability of dermoscopic patterns of eccrine poroma, and further studies are required to establish the specificity of vascularized features.

Acral lesions are more likely to show the classic clinical features of erythema and exophytic growth. A case of a collision tumor with the verrucous changes of poroma, seborrheic keratosis, and viral wart has been described.10 The verrucous changes may lead to misdiagnosis as plantar warts or other neoplasms. Clinicians also should consider conditions that are induced by friction or trauma. In our patient, dermoscopy and RCM aided in the diagnosis of eccrine poroma due to the interference of prominent overlying verrucous changes.

Treatment of poroma is optional. Deeper lesions can be treated with surgical excision, and superficial lesions may be treated with electrosurgical destruction. Our patient was treated with surgical excision followed by repair of the surgical defect with a double V-Y flap.

The Diagnosis: Eccrine Poroma

Histopathology demonstrated epidermal thickening, epidermal protrusions, a well-defined mass of tumor cells that extended from the epidermis down to the dermis, and luminal structures. Poroid cells and ovoid nuclei with basophilic cytoplasm also were evident (Figure 1). Dermoscopy showed papillomatous growth, milky-red areas, and dotted vessels (Figure 2). Reflectance confocal microscopy (RCM) at the spinous layer showed hyporefractile, dark, roundish lumina surrounded by keratinocytes (Figure 3). Based on the histologic, dermoscopic, and RCM findings, our patient was diagnosed with eccrine poroma.

Goldman et al¹ first described poroma in 1956. Poromas, which include eccrine poroma, are a group of benign cutaneous neoplasms arising from the terminal eccrine or apocrine sweat gland ducts.² Histologically, poroid cells appear as cuboidal keratinocytes with monomorphous ovoid nuclei and discrete nucleoli.³ They usually appear as nodules or plaques with colors varying from flesh colored to red, brown, or bluish, and they clinically mimic several benign and malignant skin tumors. The differential diagnosis may include keratoacanthoma, plantar wart, verrucous carcinoma, basal cell carcinoma, and squamous cell carcinoma. Poromas can be of eccrine or apocrine origin.⁴ They also belong to a broad group of neoplasms, including nodular hidradenomas, clear cell hidradenomas, hidroacanthoma simplex, dermal duct tumors, and hidradenomas.⁵ Four subtypes—poroma, poroid hidradenoma, hidroacanthoma simplex, and dermal duct tumor—have been documented.⁶ Because poromas have nonspecific and variable clinical presentations, they often are misdiagnosed as other skin neoplasms, and differentiation may be difficult. For example, some cases of poroma present with follicular, sebaceous, and/or apocrine differentiation, leading to difficulty in diagnosis.

Characteristic features of eccrine poroma seen on dermoscopy and RCM have the potential to aid in the diagnosis compared to histopathology. Marchetti et al⁷ proposed 4 patterns of characteristic dermoscopic findings. Pattern 1 refers to the classic description with bleeding spots, a structureless yellow appearance, milkyred globules, and branched vessels. Patterns 2 and 3 simulate basal cell carcinoma, dermal nevus, or vascular tumors. Pattern 4 refers to tumors that are large in size and resemble keratinizing neoplasms.⁷ Brugués et al⁸ described poromas with the following RCM findings: an atypical honeycomb shape that was well separated from the normal epithelium, hyporefractile nests with atypical cells, lack of palisading, and dark holes. One study described RCM parameters as cords without palisading, dark holes, prominent vascularization, and abundant stroma—findings that were positively associated with poroma in a univariate analysis. These findings assist in distinguishing poromas from other conditions in the differential diagnosis.⁹

There is a substantial overlap in clinical appearance with malignant conditions, including basal cell carcinoma, squamous cell carcinoma, cutaneous metastases, and Paget disease; therefore, the use of dermoscopy and RCM may be helpful in the diagnosis and recognition of specific features, as well as the corresponding patterns of poroma. Poromas commonly display vascularized features due to the variability of dermoscopic patterns of eccrine poroma, and further studies are required to establish the specificity of vascularized features.

Acral lesions are more likely to show the classic clinical features of erythema and exophytic growth. A case of a collision tumor with the verrucous changes of poroma, seborrheic keratosis, and viral wart has been described.10 The verrucous changes may lead to misdiagnosis as plantar warts or other neoplasms. Clinicians also should consider conditions that are induced by friction or trauma. In our patient, dermoscopy and RCM aided in the diagnosis of eccrine poroma due to the interference of prominent overlying verrucous changes.

Treatment of poroma is optional. Deeper lesions can be treated with surgical excision, and superficial lesions may be treated with electrosurgical destruction. Our patient was treated with surgical excision followed by repair of the surgical defect with a double V-Y flap.

The Diagnosis: Eccrine Poroma

Histopathology demonstrated epidermal thickening, epidermal protrusions, a well-defined mass of tumor cells that extended from the epidermis down to the dermis, and luminal structures. Poroid cells and ovoid nuclei with basophilic cytoplasm also were evident (Figure 1). Dermoscopy showed papillomatous growth, milky-red areas, and dotted vessels (Figure 2). Reflectance confocal microscopy (RCM) at the spinous layer showed hyporefractile, dark, roundish lumina surrounded by keratinocytes (Figure 3). Based on the histologic, dermoscopic, and RCM findings, our patient was diagnosed with eccrine poroma.

Goldman et al¹ first described poroma in 1956. Poromas, which include eccrine poroma, are a group of benign cutaneous neoplasms arising from the terminal eccrine or apocrine sweat gland ducts.² Histologically, poroid cells appear as cuboidal keratinocytes with monomorphous ovoid nuclei and discrete nucleoli.³ They usually appear as nodules or plaques with colors varying from flesh colored to red, brown, or bluish, and they clinically mimic several benign and malignant skin tumors. The differential diagnosis may include keratoacanthoma, plantar wart, verrucous carcinoma, basal cell carcinoma, and squamous cell carcinoma. Poromas can be of eccrine or apocrine origin.⁴ They also belong to a broad group of neoplasms, including nodular hidradenomas, clear cell hidradenomas, hidroacanthoma simplex, dermal duct tumors, and hidradenomas.⁵ Four subtypes—poroma, poroid hidradenoma, hidroacanthoma simplex, and dermal duct tumor—have been documented.⁶ Because poromas have nonspecific and variable clinical presentations, they often are misdiagnosed as other skin neoplasms, and differentiation may be difficult. For example, some cases of poroma present with follicular, sebaceous, and/or apocrine differentiation, leading to difficulty in diagnosis.

Characteristic features of eccrine poroma seen on dermoscopy and RCM have the potential to aid in the diagnosis compared to histopathology. Marchetti et al⁷ proposed 4 patterns of characteristic dermoscopic findings. Pattern 1 refers to the classic description with bleeding spots, a structureless yellow appearance, milkyred globules, and branched vessels. Patterns 2 and 3 simulate basal cell carcinoma, dermal nevus, or vascular tumors. Pattern 4 refers to tumors that are large in size and resemble keratinizing neoplasms.⁷ Brugués et al⁸ described poromas with the following RCM findings: an atypical honeycomb shape that was well separated from the normal epithelium, hyporefractile nests with atypical cells, lack of palisading, and dark holes. One study described RCM parameters as cords without palisading, dark holes, prominent vascularization, and abundant stroma—findings that were positively associated with poroma in a univariate analysis. These findings assist in distinguishing poromas from other conditions in the differential diagnosis.⁹

There is a substantial overlap in clinical appearance with malignant conditions, including basal cell carcinoma, squamous cell carcinoma, cutaneous metastases, and Paget disease; therefore, the use of dermoscopy and RCM may be helpful in the diagnosis and recognition of specific features, as well as the corresponding patterns of poroma. Poromas commonly display vascularized features due to the variability of dermoscopic patterns of eccrine poroma, and further studies are required to establish the specificity of vascularized features.

Acral lesions are more likely to show the classic clinical features of erythema and exophytic growth. A case of a collision tumor with the verrucous changes of poroma, seborrheic keratosis, and viral wart has been described.10 The verrucous changes may lead to misdiagnosis as plantar warts or other neoplasms. Clinicians also should consider conditions that are induced by friction or trauma. In our patient, dermoscopy and RCM aided in the diagnosis of eccrine poroma due to the interference of prominent overlying verrucous changes.

Treatment of poroma is optional. Deeper lesions can be treated with surgical excision, and superficial lesions may be treated with electrosurgical destruction. Our patient was treated with surgical excision followed by repair of the surgical defect with a double V-Y flap.

CHICAGO – The US Department of Veterans Affairs (VA) top medical officer told the Association of VA Hematology/Oncology (AVAHO) oncology members that they are at the forefront of the agency’s push to expand care for veterans who may have been injured by exposure to hazardous materials on the job.

“All of you are playing a critical role in implementing the PACT Act, the signature legislative achievement of the Biden administration,” said Shereef Elnahal, MD, MBA, the VA Under Secretary for Health, in a keynote address at the 2023 annual meeting of AVAHO. “But more importantly, if we do our jobs right, it could be the largest expansion of veterans’ benefits in the history of this country. That requires us to have the capacity to deliver care to so many more individuals.”

The VA has provided more than 4.1 million free toxic exposure screenings to veterans since President Biden signed the PACT Act (The Sergeant First Class Heath Robinson Honoring our Promise to Address Comprehensive Toxics Act) in August 2022. The legislation prioritizes claims for cancer, terminal illnesses, and homelessness, and the White House says it has allowed the Veterans Health Administration and the Veterans Benefits Administration to grow at the fastest rates in 2 decades. 

“Almost every type of solid tumor is now considered a presumptive condition associated with burden of exposure to veterans deployed anywhere in Central Command, either in the Persian Gulf War or the post-9/11 conflicts,” said Under Secretary Elnahal, who was confirmed in his job by the Senate in July 2022. 

Implementing the PACT Act “requires all of us to make investments and further strengthen our system’s care for oncology,” he said. It is also crucial, to reduce “leakage into the community,” referring to veterans who leave the VA for private care. “I know for a fact that the care that veterans get when they have oncology services available in our direct-care system within VA is better. That's not a contention. That is proven by different peer-reviewed studies over the years. And I think that comparison is only intensifying when it comes to how much better evidence-based care our veterans receive at the hands of all of you across the country.”

Elnahal highlighted the development of a “2-way” cancer registry that will allow the National Institute and the VA to exchange cancer diagnosis and treatment data with state registries. “This will give the VA access to critical data in a complete way—to what veterans have experienced, especially veterans who are getting parts of their care in one place and parts of their care in a different place.”

On the data front, he also noted that “the PACT Act also requires us to research the future and determine the next set of presumptive conditions that are related to the hazards of serving our country. It requires that we have robust data sets to be able to gain those insights.”
More globally, Elnahal said the VA can play a crucial role in the Cancer Moonshot Program: “We can win the race, and VA can contribute asymmetrically to that race, to make cancer a chronic condition.”

He highlighted efforts within the VA to battle cancer such as programs to reduce disparities, boost cancer screening, treat rural veterans via a national teleoncology service, and implement the Close to Me program to bring infusion services to veterans in isolated regions.

But Elnahal’s presentation was not entirely rosy. He warned that 40% of veterans are being served outside the VA. “That's sort of a rule-of-thumb threshold when you start looking more like a payer than a provider.”

He also noted that while the VA hired 54,000 people in just the past year—6.2% growth—it takes a long time to bring workers on board. “That’s why I'm holding every single leader in our system accountable for reducing onboarding times by at least a month,” he said. The AVAHO audience enthusiastically applauded.

CHICAGO – The US Department of Veterans Affairs (VA) top medical officer told the Association of VA Hematology/Oncology (AVAHO) oncology members that they are at the forefront of the agency’s push to expand care for veterans who may have been injured by exposure to hazardous materials on the job.

“All of you are playing a critical role in implementing the PACT Act, the signature legislative achievement of the Biden administration,” said Shereef Elnahal, MD, MBA, the VA Under Secretary for Health, in a keynote address at the 2023 annual meeting of AVAHO. “But more importantly, if we do our jobs right, it could be the largest expansion of veterans’ benefits in the history of this country. That requires us to have the capacity to deliver care to so many more individuals.”

The VA has provided more than 4.1 million free toxic exposure screenings to veterans since President Biden signed the PACT Act (The Sergeant First Class Heath Robinson Honoring our Promise to Address Comprehensive Toxics Act) in August 2022. The legislation prioritizes claims for cancer, terminal illnesses, and homelessness, and the White House says it has allowed the Veterans Health Administration and the Veterans Benefits Administration to grow at the fastest rates in 2 decades. 

“Almost every type of solid tumor is now considered a presumptive condition associated with burden of exposure to veterans deployed anywhere in Central Command, either in the Persian Gulf War or the post-9/11 conflicts,” said Under Secretary Elnahal, who was confirmed in his job by the Senate in July 2022. 

Implementing the PACT Act “requires all of us to make investments and further strengthen our system’s care for oncology,” he said. It is also crucial, to reduce “leakage into the community,” referring to veterans who leave the VA for private care. “I know for a fact that the care that veterans get when they have oncology services available in our direct-care system within VA is better. That's not a contention. That is proven by different peer-reviewed studies over the years. And I think that comparison is only intensifying when it comes to how much better evidence-based care our veterans receive at the hands of all of you across the country.”

Elnahal highlighted the development of a “2-way” cancer registry that will allow the National Institute and the VA to exchange cancer diagnosis and treatment data with state registries. “This will give the VA access to critical data in a complete way—to what veterans have experienced, especially veterans who are getting parts of their care in one place and parts of their care in a different place.”

On the data front, he also noted that “the PACT Act also requires us to research the future and determine the next set of presumptive conditions that are related to the hazards of serving our country. It requires that we have robust data sets to be able to gain those insights.”
More globally, Elnahal said the VA can play a crucial role in the Cancer Moonshot Program: “We can win the race, and VA can contribute asymmetrically to that race, to make cancer a chronic condition.”

He highlighted efforts within the VA to battle cancer such as programs to reduce disparities, boost cancer screening, treat rural veterans via a national teleoncology service, and implement the Close to Me program to bring infusion services to veterans in isolated regions.

But Elnahal’s presentation was not entirely rosy. He warned that 40% of veterans are being served outside the VA. “That's sort of a rule-of-thumb threshold when you start looking more like a payer than a provider.”

He also noted that while the VA hired 54,000 people in just the past year—6.2% growth—it takes a long time to bring workers on board. “That’s why I'm holding every single leader in our system accountable for reducing onboarding times by at least a month,” he said. The AVAHO audience enthusiastically applauded.

CHICAGO – The US Department of Veterans Affairs (VA) top medical officer told the Association of VA Hematology/Oncology (AVAHO) oncology members that they are at the forefront of the agency’s push to expand care for veterans who may have been injured by exposure to hazardous materials on the job.

“All of you are playing a critical role in implementing the PACT Act, the signature legislative achievement of the Biden administration,” said Shereef Elnahal, MD, MBA, the VA Under Secretary for Health, in a keynote address at the 2023 annual meeting of AVAHO. “But more importantly, if we do our jobs right, it could be the largest expansion of veterans’ benefits in the history of this country. That requires us to have the capacity to deliver care to so many more individuals.”

The VA has provided more than 4.1 million free toxic exposure screenings to veterans since President Biden signed the PACT Act (The Sergeant First Class Heath Robinson Honoring our Promise to Address Comprehensive Toxics Act) in August 2022. The legislation prioritizes claims for cancer, terminal illnesses, and homelessness, and the White House says it has allowed the Veterans Health Administration and the Veterans Benefits Administration to grow at the fastest rates in 2 decades. 

“Almost every type of solid tumor is now considered a presumptive condition associated with burden of exposure to veterans deployed anywhere in Central Command, either in the Persian Gulf War or the post-9/11 conflicts,” said Under Secretary Elnahal, who was confirmed in his job by the Senate in July 2022. 

Implementing the PACT Act “requires all of us to make investments and further strengthen our system’s care for oncology,” he said. It is also crucial, to reduce “leakage into the community,” referring to veterans who leave the VA for private care. “I know for a fact that the care that veterans get when they have oncology services available in our direct-care system within VA is better. That's not a contention. That is proven by different peer-reviewed studies over the years. And I think that comparison is only intensifying when it comes to how much better evidence-based care our veterans receive at the hands of all of you across the country.”

Elnahal highlighted the development of a “2-way” cancer registry that will allow the National Institute and the VA to exchange cancer diagnosis and treatment data with state registries. “This will give the VA access to critical data in a complete way—to what veterans have experienced, especially veterans who are getting parts of their care in one place and parts of their care in a different place.”

On the data front, he also noted that “the PACT Act also requires us to research the future and determine the next set of presumptive conditions that are related to the hazards of serving our country. It requires that we have robust data sets to be able to gain those insights.”
More globally, Elnahal said the VA can play a crucial role in the Cancer Moonshot Program: “We can win the race, and VA can contribute asymmetrically to that race, to make cancer a chronic condition.”

He highlighted efforts within the VA to battle cancer such as programs to reduce disparities, boost cancer screening, treat rural veterans via a national teleoncology service, and implement the Close to Me program to bring infusion services to veterans in isolated regions.

But Elnahal’s presentation was not entirely rosy. He warned that 40% of veterans are being served outside the VA. “That's sort of a rule-of-thumb threshold when you start looking more like a payer than a provider.”

He also noted that while the VA hired 54,000 people in just the past year—6.2% growth—it takes a long time to bring workers on board. “That’s why I'm holding every single leader in our system accountable for reducing onboarding times by at least a month,” he said. The AVAHO audience enthusiastically applauded.

The question looms large for patients with stable systemic lupus erythematosus (SLE): to taper or not to taper corticosteroids or immunosuppressive therapy? For patients and the physicians treating them, the evidence points in both directions. Flares are exacerbated by tapering, but simultaneously organ damage is tempered. Where is the balance? What competing factors together inform decision-making?

A recent multinational, observational cohort study conducted by Jiacai Cho, MBBS, of National University Hospital, Singapore, and colleagues, and published in The Lancet Rheumatology concluded that, given the odds of excess flares associated with tapering of corticosteroids and immunosuppressive therapy in patients with stable SLE, drug tapering warrants careful consideration of risks and benefits and is best reserved for those in complete clinical and serological remission with stable disease for at least 6 months. However, in an accompanying editorial, Yann Nguyen, MD, MPH, and Nathalie Costedoat-Chalumeau, MD, PhD, of the National Referral Center for Rare Autoimmune and Systemic Diseases at Cochin Hospital, Paris, and the Center for Research in Epidemiology and Statistics at Paris City University, argued for tipping the scale back from some of those expressed cautions.

Bruce Jancin/MDedge News

In interviews, experts in the field expressed both strong appreciation for the cohort study and, like the editorialists, cognizance of its limitations.

Dr. Cho and colleagues recruited 3,002 adult patients with SLE (92.2% female, median age 39.5 years), from 25 sites across 13 Asia-Pacific countries. They were receiving routine clinical care and had achieved stable disease in at least one of two or more visits. Stable disease was defined by meeting criteria for Lupus Low Disease Activity State (LLDAS; SLE Disease Activity Index 2000 [SLEDAI-2K] score ≤ 4, Physician Global Assessment [PGA] ≤ 1, and prednisolone ≤ 7.5 mg/day), the 2021 DORIS definition of remission (clinical SLEDAI-2K score 0, PGA score < 0.5, and prednisolone dose ≤ 5 mg/day), or DORIS complete remission on therapy (SLEDAI-2K score 0, PGA score < 0.5, and prednisolone dose ≤ 5 mg/day). Any decrease in dose of corticosteroids or immunosuppressive therapy (mycophenolate mofetil, calcineurin inhibitors, azathioprine, leflunomide, or methotrexate) defined tapering. The investigators compared the odds of disease flares (SELENA-SLEDAI Flare Index) at the visit following tapering among those with tapering versus those who had continued the same drug doses.
 

Higher odds of flare with tapering

Tapering, compared with continuing with the same dose, was clearly associated with higher odds of flare at the next visit (11.4% with continuing vs. 17.0% with tapering; odds ratio, 1.24; 95% confidence interval, 1.10-1.39; P = .0005). Flares among patients who tapered were also slightly more often severe than with continuing the same dose (21.5% of flares vs. 19.7%). The level of remission at the time of tapering also mattered. Of 2,095 continuous tapering attempts, 860 (41.1%) were initiated in LLDAS, 596 (28.4%) in remission, and 639 (30.5%) in complete remission. Tapering when in LLDAS or remission, compared with complete remission, was associated with a higher likelihood of flare by 1 year (LLDAS: OR, 1.37; 95% CI, 1.03-1.81; P = .029; and remission: OR, 1.45; 95% CI, 1.08-1.94; P = .013). Time to first flare followed the same pattern. Also, sustained LLDAS, remission, or complete remission for at least 6 months just before the time of taper was associated with lower odds of flare at next visit and flares in 1 year, and longer time to flare.

Take baseline disease status, hydroxychloroquine’s effect into account

Dr. Nguyen and Dr. Costedoat-Chalumeau underscored several factors that may soften the risk for flares seen with tapering. They pointed to higher baseline doses of prednisone and immunosuppressants (and thus likely more severe disease that is more likely to flare) in the patients with tapering. Also, the SELENA-SLEDAI Flare Index used in the study classifies some clinically insignificant flares as mild to moderate and ignores the benefit of tapering. (It classifies patients as having a severe flare even when starting a new immunosuppressant prescription, such as azathioprine, methotrexate, or both, in an effort to reduce corticosteroid use.) They wrote that the study did not assess the rate of clinically meaningful flares (“essentially renal flares”), nor did it highlight that the “tiny” increase in absolute risk of severe flares (from 2.2% to 3.7%) could be further contextualized by the offset of the smaller, unmeasured rate of clinically significant flares and the “extremely relevant” risk of concomitant damage from prolonged treatment.

Dr. Nguyen and Dr. Costedoat-Chalumeau urged hydroxychloroquine use for all patients unless clearly contraindicated. In their own research, they have detailed hydroxychloroquine benefits in reducing not only flare risk, but also comorbidities, damage, and mortality. In the current study, the prevalence of hydroxychloroquine use in all the patient visits was only 63.3%. “We can assume that if more patients had been treated with hydroxychloroquine, both the number of flares and the difference between the two strategies would have been lower,” they wrote. They cited findings from a study of patients in remission for 2 years or longer in the Toronto Lupus Cohort in which a gradual taper of corticosteroids over 1 year was safe and feasible and resulted in less damage accrual at 24 months than not tapering. Optimizing tapering can minimize flare risk, they concluded.

McGill University Health Center

Tapering SLE medications always involves some chance of flare and has to be considered a calculated risk, Sasha Bernatsky, MD, the James McGill professor of medicine in the division of rheumatology at McGill University, Montreal, said in an interview. “Long-term prednisone is not good for patients. I have heard it called ‘the miracle drug from hell’ – meaning that, yes, it controls disease, but at a cost of long-term complications. So we must be conscientious about tapering prednisone.” She observed that in the short-term, there may not be a huge risk to keeping a patient on an antimalarial and counseling patients to stay on it because their risk of flare is higher if they taper. Rheumatologists usually agree, however, that after 10 years or more, there is a real chance of retinal toxicity. “In our Montreal cohort, the risk of retinal toxicity was 5% after an average of 12.8 years of antimalarial use. My concern is that if a patient develops SLE in their 20s, how do we decide if we should keep them on an antimalarial for the next 60 or 70 years? If we keep them on the drug from age 25 to 45, and they then get retinal toxicity, they would essentially never be able to be on the drug again. So I do try to keep patients on the lowest dose of an antimalarial that is possible.”

Dr. Bernatsky pointed out further, “We think about tapering other immunosuppressants (such as methotrexate or mycophenolate or azathioprine) quite differently than prednisone tapering. We take our time a bit more, since many patients will tolerate being on standard doses of these drugs fairly well. If or when we do consider tapering these drugs, both our intuition and the literature suggests that someone with worse baseline disease activity or severity, who has needed a lot of steroids and multiple combinations of drugs to control disease, has a higher chance of flaring than someone with milder disease. As the editorial points out, lupus physicians (and their patients) need to think carefully about the patient’s risk profile, and be sure to tailor follow-up based on flare risk.”

Frank discussions with patients about the risks of tapering are needed, she said. “On one hand, there is consensus about how some aspects of lupus should be managed (for example, aggressive treatment of severe nephritis), but on the other hand, when it comes to long-term management and especially discussing tapering, we must have good discussions with patients. When a patient asks if they can taper a drug – many just lower or stop their drugs without asking – I am as honest as I can be, but ultimately have to admit any taper could be associated with a flare. It’s helpful to have actual figures to discuss with patients.”
 

No surprises

“This is an interesting study, which did not produce any surprises,” Dafna D. Gladman, MD, professor of medicine at University of Toronto and senior scientist at the university’s Schroeder Arthritis Institute, said when asked to comment. “We already knew from previous studies that abrupt withdrawal is not a good idea, and that if you taper when a patient is under conditions of remission, the rate of flare is actually lower than the usual rate of flare that occurs in people who continue on these medications. But the major limitation is that they did not specifically look at those who we would taper in clinical practice. In addition, they do not specify that the patients had to be on low-dose glucocorticoids before tapering, and they combined both immunosuppressive and steroids. It is not clear from the study what the excess flare rate was, or whether the flares were mild or severe. Most flares in patients with SLE are mild, consisting of skin and joint manifestations, while only a few patients have flares in kidney or neurologic manifestations.”

Dr. Gladman described her approach to tapering: “We aim for our patients to be taking no more than 5 mg of prednisone and to be in at least clinical remission with a SLEDAI-2K of 0 for at least 2 years before we would taper to glucocorticoids withdrawal. We always withdraw glucocorticoids first and immunosuppressives later, and keep patients on antimalarials the longest, unless there are specific side effects to the immunosuppressive or antimalarials which require their cessation earlier.”
 

Uncertainty persists

Other SLE experts weighing in confirmed the view that future research should aim to achieve clarity about the relative risks and benefits of tapering SLE drug regimens to maintain disease remission while minimizing potential for organ damage.

Oklahoma Medical Research Foundation

“Steroids are our friend and our enemy,” Joan T. Merrill, MD, professor of medicine at the University of Oklahoma Health Sciences Center, Oklahoma City, said in an interview. “If a person with lupus is in a lot of trouble, corticosteroids are almost universally a good option to get them out. But for too many decades, for too many patients, despite all the improvements we have made in better understanding the disease and developing some promising new treatments, we have yet to shed the inexorable toxicity in multiple organs of steroid dependence.” She continued, “Corticosteroids, even at low dose, may have broad-spectrum effects. But, in fact, so do many of the more ‘targeted’ agents. If all patients were lined up at the beginning of a study while being given azathioprine or a calcineurin inhibitor or belimumab at a stable, tolerable dose, you might see the same data if you tapered that agent down. What we really need is improved individualized guidance about when and how fast to remove immune modulators from stable patients with lupus without disturbing the balance that had been achieved in such a quiescent patient.”

Cedars-Sinai Medical Center

That enduring uncertainty was echoed by Daniel J. Wallace, MD, professor of medicine at Cedars-Sinai Medical Center, Los Angeles: “The take-home message from this interesting paper,” he commented, “is that current lupus biomarkers are not adequate. They do not guide the practitioner well enough, so that all too often medication regimens are tapered even though the risks are not really well known. Also, there is evidence in the literature that fibrosis and ‘damage’ progress even if acute phase reactants such as sedimentation rate, [C-reactive protein], complement 3 and 4, and anti-dsDNA are normal. We don’t have a good metric to detect them.”

Dr. Cho and colleagues’ study was funded by AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen, Merck Serono, GlaxoSmithKline, and UCB. Dr. Gladman disclosed consulting and/or research support from AbbVie, Amgen, Bristol-Myers Squibb, Eli Lilly, Janssen, Novartis, Pfizer, and UCB.

The question looms large for patients with stable systemic lupus erythematosus (SLE): to taper or not to taper corticosteroids or immunosuppressive therapy? For patients and the physicians treating them, the evidence points in both directions. Flares are exacerbated by tapering, but simultaneously organ damage is tempered. Where is the balance? What competing factors together inform decision-making?

A recent multinational, observational cohort study conducted by Jiacai Cho, MBBS, of National University Hospital, Singapore, and colleagues, and published in The Lancet Rheumatology concluded that, given the odds of excess flares associated with tapering of corticosteroids and immunosuppressive therapy in patients with stable SLE, drug tapering warrants careful consideration of risks and benefits and is best reserved for those in complete clinical and serological remission with stable disease for at least 6 months. However, in an accompanying editorial, Yann Nguyen, MD, MPH, and Nathalie Costedoat-Chalumeau, MD, PhD, of the National Referral Center for Rare Autoimmune and Systemic Diseases at Cochin Hospital, Paris, and the Center for Research in Epidemiology and Statistics at Paris City University, argued for tipping the scale back from some of those expressed cautions.

Bruce Jancin/MDedge News

In interviews, experts in the field expressed both strong appreciation for the cohort study and, like the editorialists, cognizance of its limitations.

Dr. Cho and colleagues recruited 3,002 adult patients with SLE (92.2% female, median age 39.5 years), from 25 sites across 13 Asia-Pacific countries. They were receiving routine clinical care and had achieved stable disease in at least one of two or more visits. Stable disease was defined by meeting criteria for Lupus Low Disease Activity State (LLDAS; SLE Disease Activity Index 2000 [SLEDAI-2K] score ≤ 4, Physician Global Assessment [PGA] ≤ 1, and prednisolone ≤ 7.5 mg/day), the 2021 DORIS definition of remission (clinical SLEDAI-2K score 0, PGA score < 0.5, and prednisolone dose ≤ 5 mg/day), or DORIS complete remission on therapy (SLEDAI-2K score 0, PGA score < 0.5, and prednisolone dose ≤ 5 mg/day). Any decrease in dose of corticosteroids or immunosuppressive therapy (mycophenolate mofetil, calcineurin inhibitors, azathioprine, leflunomide, or methotrexate) defined tapering. The investigators compared the odds of disease flares (SELENA-SLEDAI Flare Index) at the visit following tapering among those with tapering versus those who had continued the same drug doses.
 

Higher odds of flare with tapering

Tapering, compared with continuing with the same dose, was clearly associated with higher odds of flare at the next visit (11.4% with continuing vs. 17.0% with tapering; odds ratio, 1.24; 95% confidence interval, 1.10-1.39; P = .0005). Flares among patients who tapered were also slightly more often severe than with continuing the same dose (21.5% of flares vs. 19.7%). The level of remission at the time of tapering also mattered. Of 2,095 continuous tapering attempts, 860 (41.1%) were initiated in LLDAS, 596 (28.4%) in remission, and 639 (30.5%) in complete remission. Tapering when in LLDAS or remission, compared with complete remission, was associated with a higher likelihood of flare by 1 year (LLDAS: OR, 1.37; 95% CI, 1.03-1.81; P = .029; and remission: OR, 1.45; 95% CI, 1.08-1.94; P = .013). Time to first flare followed the same pattern. Also, sustained LLDAS, remission, or complete remission for at least 6 months just before the time of taper was associated with lower odds of flare at next visit and flares in 1 year, and longer time to flare.

Take baseline disease status, hydroxychloroquine’s effect into account

Dr. Nguyen and Dr. Costedoat-Chalumeau underscored several factors that may soften the risk for flares seen with tapering. They pointed to higher baseline doses of prednisone and immunosuppressants (and thus likely more severe disease that is more likely to flare) in the patients with tapering. Also, the SELENA-SLEDAI Flare Index used in the study classifies some clinically insignificant flares as mild to moderate and ignores the benefit of tapering. (It classifies patients as having a severe flare even when starting a new immunosuppressant prescription, such as azathioprine, methotrexate, or both, in an effort to reduce corticosteroid use.) They wrote that the study did not assess the rate of clinically meaningful flares (“essentially renal flares”), nor did it highlight that the “tiny” increase in absolute risk of severe flares (from 2.2% to 3.7%) could be further contextualized by the offset of the smaller, unmeasured rate of clinically significant flares and the “extremely relevant” risk of concomitant damage from prolonged treatment.

Dr. Nguyen and Dr. Costedoat-Chalumeau urged hydroxychloroquine use for all patients unless clearly contraindicated. In their own research, they have detailed hydroxychloroquine benefits in reducing not only flare risk, but also comorbidities, damage, and mortality. In the current study, the prevalence of hydroxychloroquine use in all the patient visits was only 63.3%. “We can assume that if more patients had been treated with hydroxychloroquine, both the number of flares and the difference between the two strategies would have been lower,” they wrote. They cited findings from a study of patients in remission for 2 years or longer in the Toronto Lupus Cohort in which a gradual taper of corticosteroids over 1 year was safe and feasible and resulted in less damage accrual at 24 months than not tapering. Optimizing tapering can minimize flare risk, they concluded.

McGill University Health Center

Tapering SLE medications always involves some chance of flare and has to be considered a calculated risk, Sasha Bernatsky, MD, the James McGill professor of medicine in the division of rheumatology at McGill University, Montreal, said in an interview. “Long-term prednisone is not good for patients. I have heard it called ‘the miracle drug from hell’ – meaning that, yes, it controls disease, but at a cost of long-term complications. So we must be conscientious about tapering prednisone.” She observed that in the short-term, there may not be a huge risk to keeping a patient on an antimalarial and counseling patients to stay on it because their risk of flare is higher if they taper. Rheumatologists usually agree, however, that after 10 years or more, there is a real chance of retinal toxicity. “In our Montreal cohort, the risk of retinal toxicity was 5% after an average of 12.8 years of antimalarial use. My concern is that if a patient develops SLE in their 20s, how do we decide if we should keep them on an antimalarial for the next 60 or 70 years? If we keep them on the drug from age 25 to 45, and they then get retinal toxicity, they would essentially never be able to be on the drug again. So I do try to keep patients on the lowest dose of an antimalarial that is possible.”

Dr. Bernatsky pointed out further, “We think about tapering other immunosuppressants (such as methotrexate or mycophenolate or azathioprine) quite differently than prednisone tapering. We take our time a bit more, since many patients will tolerate being on standard doses of these drugs fairly well. If or when we do consider tapering these drugs, both our intuition and the literature suggests that someone with worse baseline disease activity or severity, who has needed a lot of steroids and multiple combinations of drugs to control disease, has a higher chance of flaring than someone with milder disease. As the editorial points out, lupus physicians (and their patients) need to think carefully about the patient’s risk profile, and be sure to tailor follow-up based on flare risk.”

Frank discussions with patients about the risks of tapering are needed, she said. “On one hand, there is consensus about how some aspects of lupus should be managed (for example, aggressive treatment of severe nephritis), but on the other hand, when it comes to long-term management and especially discussing tapering, we must have good discussions with patients. When a patient asks if they can taper a drug – many just lower or stop their drugs without asking – I am as honest as I can be, but ultimately have to admit any taper could be associated with a flare. It’s helpful to have actual figures to discuss with patients.”
 

No surprises

“This is an interesting study, which did not produce any surprises,” Dafna D. Gladman, MD, professor of medicine at University of Toronto and senior scientist at the university’s Schroeder Arthritis Institute, said when asked to comment. “We already knew from previous studies that abrupt withdrawal is not a good idea, and that if you taper when a patient is under conditions of remission, the rate of flare is actually lower than the usual rate of flare that occurs in people who continue on these medications. But the major limitation is that they did not specifically look at those who we would taper in clinical practice. In addition, they do not specify that the patients had to be on low-dose glucocorticoids before tapering, and they combined both immunosuppressive and steroids. It is not clear from the study what the excess flare rate was, or whether the flares were mild or severe. Most flares in patients with SLE are mild, consisting of skin and joint manifestations, while only a few patients have flares in kidney or neurologic manifestations.”

Dr. Gladman described her approach to tapering: “We aim for our patients to be taking no more than 5 mg of prednisone and to be in at least clinical remission with a SLEDAI-2K of 0 for at least 2 years before we would taper to glucocorticoids withdrawal. We always withdraw glucocorticoids first and immunosuppressives later, and keep patients on antimalarials the longest, unless there are specific side effects to the immunosuppressive or antimalarials which require their cessation earlier.”
 

Uncertainty persists

Other SLE experts weighing in confirmed the view that future research should aim to achieve clarity about the relative risks and benefits of tapering SLE drug regimens to maintain disease remission while minimizing potential for organ damage.

Oklahoma Medical Research Foundation

“Steroids are our friend and our enemy,” Joan T. Merrill, MD, professor of medicine at the University of Oklahoma Health Sciences Center, Oklahoma City, said in an interview. “If a person with lupus is in a lot of trouble, corticosteroids are almost universally a good option to get them out. But for too many decades, for too many patients, despite all the improvements we have made in better understanding the disease and developing some promising new treatments, we have yet to shed the inexorable toxicity in multiple organs of steroid dependence.” She continued, “Corticosteroids, even at low dose, may have broad-spectrum effects. But, in fact, so do many of the more ‘targeted’ agents. If all patients were lined up at the beginning of a study while being given azathioprine or a calcineurin inhibitor or belimumab at a stable, tolerable dose, you might see the same data if you tapered that agent down. What we really need is improved individualized guidance about when and how fast to remove immune modulators from stable patients with lupus without disturbing the balance that had been achieved in such a quiescent patient.”

Cedars-Sinai Medical Center

That enduring uncertainty was echoed by Daniel J. Wallace, MD, professor of medicine at Cedars-Sinai Medical Center, Los Angeles: “The take-home message from this interesting paper,” he commented, “is that current lupus biomarkers are not adequate. They do not guide the practitioner well enough, so that all too often medication regimens are tapered even though the risks are not really well known. Also, there is evidence in the literature that fibrosis and ‘damage’ progress even if acute phase reactants such as sedimentation rate, [C-reactive protein], complement 3 and 4, and anti-dsDNA are normal. We don’t have a good metric to detect them.”

Dr. Cho and colleagues’ study was funded by AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen, Merck Serono, GlaxoSmithKline, and UCB. Dr. Gladman disclosed consulting and/or research support from AbbVie, Amgen, Bristol-Myers Squibb, Eli Lilly, Janssen, Novartis, Pfizer, and UCB.

The question looms large for patients with stable systemic lupus erythematosus (SLE): to taper or not to taper corticosteroids or immunosuppressive therapy? For patients and the physicians treating them, the evidence points in both directions. Flares are exacerbated by tapering, but simultaneously organ damage is tempered. Where is the balance? What competing factors together inform decision-making?

A recent multinational, observational cohort study conducted by Jiacai Cho, MBBS, of National University Hospital, Singapore, and colleagues, and published in The Lancet Rheumatology concluded that, given the odds of excess flares associated with tapering of corticosteroids and immunosuppressive therapy in patients with stable SLE, drug tapering warrants careful consideration of risks and benefits and is best reserved for those in complete clinical and serological remission with stable disease for at least 6 months. However, in an accompanying editorial, Yann Nguyen, MD, MPH, and Nathalie Costedoat-Chalumeau, MD, PhD, of the National Referral Center for Rare Autoimmune and Systemic Diseases at Cochin Hospital, Paris, and the Center for Research in Epidemiology and Statistics at Paris City University, argued for tipping the scale back from some of those expressed cautions.

Bruce Jancin/MDedge News

In interviews, experts in the field expressed both strong appreciation for the cohort study and, like the editorialists, cognizance of its limitations.

Dr. Cho and colleagues recruited 3,002 adult patients with SLE (92.2% female, median age 39.5 years), from 25 sites across 13 Asia-Pacific countries. They were receiving routine clinical care and had achieved stable disease in at least one of two or more visits. Stable disease was defined by meeting criteria for Lupus Low Disease Activity State (LLDAS; SLE Disease Activity Index 2000 [SLEDAI-2K] score ≤ 4, Physician Global Assessment [PGA] ≤ 1, and prednisolone ≤ 7.5 mg/day), the 2021 DORIS definition of remission (clinical SLEDAI-2K score 0, PGA score < 0.5, and prednisolone dose ≤ 5 mg/day), or DORIS complete remission on therapy (SLEDAI-2K score 0, PGA score < 0.5, and prednisolone dose ≤ 5 mg/day). Any decrease in dose of corticosteroids or immunosuppressive therapy (mycophenolate mofetil, calcineurin inhibitors, azathioprine, leflunomide, or methotrexate) defined tapering. The investigators compared the odds of disease flares (SELENA-SLEDAI Flare Index) at the visit following tapering among those with tapering versus those who had continued the same drug doses.
 

Higher odds of flare with tapering

Tapering, compared with continuing with the same dose, was clearly associated with higher odds of flare at the next visit (11.4% with continuing vs. 17.0% with tapering; odds ratio, 1.24; 95% confidence interval, 1.10-1.39; P = .0005). Flares among patients who tapered were also slightly more often severe than with continuing the same dose (21.5% of flares vs. 19.7%). The level of remission at the time of tapering also mattered. Of 2,095 continuous tapering attempts, 860 (41.1%) were initiated in LLDAS, 596 (28.4%) in remission, and 639 (30.5%) in complete remission. Tapering when in LLDAS or remission, compared with complete remission, was associated with a higher likelihood of flare by 1 year (LLDAS: OR, 1.37; 95% CI, 1.03-1.81; P = .029; and remission: OR, 1.45; 95% CI, 1.08-1.94; P = .013). Time to first flare followed the same pattern. Also, sustained LLDAS, remission, or complete remission for at least 6 months just before the time of taper was associated with lower odds of flare at next visit and flares in 1 year, and longer time to flare.

Take baseline disease status, hydroxychloroquine’s effect into account

Dr. Nguyen and Dr. Costedoat-Chalumeau underscored several factors that may soften the risk for flares seen with tapering. They pointed to higher baseline doses of prednisone and immunosuppressants (and thus likely more severe disease that is more likely to flare) in the patients with tapering. Also, the SELENA-SLEDAI Flare Index used in the study classifies some clinically insignificant flares as mild to moderate and ignores the benefit of tapering. (It classifies patients as having a severe flare even when starting a new immunosuppressant prescription, such as azathioprine, methotrexate, or both, in an effort to reduce corticosteroid use.) They wrote that the study did not assess the rate of clinically meaningful flares (“essentially renal flares”), nor did it highlight that the “tiny” increase in absolute risk of severe flares (from 2.2% to 3.7%) could be further contextualized by the offset of the smaller, unmeasured rate of clinically significant flares and the “extremely relevant” risk of concomitant damage from prolonged treatment.

Dr. Nguyen and Dr. Costedoat-Chalumeau urged hydroxychloroquine use for all patients unless clearly contraindicated. In their own research, they have detailed hydroxychloroquine benefits in reducing not only flare risk, but also comorbidities, damage, and mortality. In the current study, the prevalence of hydroxychloroquine use in all the patient visits was only 63.3%. “We can assume that if more patients had been treated with hydroxychloroquine, both the number of flares and the difference between the two strategies would have been lower,” they wrote. They cited findings from a study of patients in remission for 2 years or longer in the Toronto Lupus Cohort in which a gradual taper of corticosteroids over 1 year was safe and feasible and resulted in less damage accrual at 24 months than not tapering. Optimizing tapering can minimize flare risk, they concluded.

McGill University Health Center

Tapering SLE medications always involves some chance of flare and has to be considered a calculated risk, Sasha Bernatsky, MD, the James McGill professor of medicine in the division of rheumatology at McGill University, Montreal, said in an interview. “Long-term prednisone is not good for patients. I have heard it called ‘the miracle drug from hell’ – meaning that, yes, it controls disease, but at a cost of long-term complications. So we must be conscientious about tapering prednisone.” She observed that in the short-term, there may not be a huge risk to keeping a patient on an antimalarial and counseling patients to stay on it because their risk of flare is higher if they taper. Rheumatologists usually agree, however, that after 10 years or more, there is a real chance of retinal toxicity. “In our Montreal cohort, the risk of retinal toxicity was 5% after an average of 12.8 years of antimalarial use. My concern is that if a patient develops SLE in their 20s, how do we decide if we should keep them on an antimalarial for the next 60 or 70 years? If we keep them on the drug from age 25 to 45, and they then get retinal toxicity, they would essentially never be able to be on the drug again. So I do try to keep patients on the lowest dose of an antimalarial that is possible.”

Dr. Bernatsky pointed out further, “We think about tapering other immunosuppressants (such as methotrexate or mycophenolate or azathioprine) quite differently than prednisone tapering. We take our time a bit more, since many patients will tolerate being on standard doses of these drugs fairly well. If or when we do consider tapering these drugs, both our intuition and the literature suggests that someone with worse baseline disease activity or severity, who has needed a lot of steroids and multiple combinations of drugs to control disease, has a higher chance of flaring than someone with milder disease. As the editorial points out, lupus physicians (and their patients) need to think carefully about the patient’s risk profile, and be sure to tailor follow-up based on flare risk.”

Frank discussions with patients about the risks of tapering are needed, she said. “On one hand, there is consensus about how some aspects of lupus should be managed (for example, aggressive treatment of severe nephritis), but on the other hand, when it comes to long-term management and especially discussing tapering, we must have good discussions with patients. When a patient asks if they can taper a drug – many just lower or stop their drugs without asking – I am as honest as I can be, but ultimately have to admit any taper could be associated with a flare. It’s helpful to have actual figures to discuss with patients.”
 

No surprises

“This is an interesting study, which did not produce any surprises,” Dafna D. Gladman, MD, professor of medicine at University of Toronto and senior scientist at the university’s Schroeder Arthritis Institute, said when asked to comment. “We already knew from previous studies that abrupt withdrawal is not a good idea, and that if you taper when a patient is under conditions of remission, the rate of flare is actually lower than the usual rate of flare that occurs in people who continue on these medications. But the major limitation is that they did not specifically look at those who we would taper in clinical practice. In addition, they do not specify that the patients had to be on low-dose glucocorticoids before tapering, and they combined both immunosuppressive and steroids. It is not clear from the study what the excess flare rate was, or whether the flares were mild or severe. Most flares in patients with SLE are mild, consisting of skin and joint manifestations, while only a few patients have flares in kidney or neurologic manifestations.”

Dr. Gladman described her approach to tapering: “We aim for our patients to be taking no more than 5 mg of prednisone and to be in at least clinical remission with a SLEDAI-2K of 0 for at least 2 years before we would taper to glucocorticoids withdrawal. We always withdraw glucocorticoids first and immunosuppressives later, and keep patients on antimalarials the longest, unless there are specific side effects to the immunosuppressive or antimalarials which require their cessation earlier.”
 

Uncertainty persists

Other SLE experts weighing in confirmed the view that future research should aim to achieve clarity about the relative risks and benefits of tapering SLE drug regimens to maintain disease remission while minimizing potential for organ damage.

Oklahoma Medical Research Foundation

“Steroids are our friend and our enemy,” Joan T. Merrill, MD, professor of medicine at the University of Oklahoma Health Sciences Center, Oklahoma City, said in an interview. “If a person with lupus is in a lot of trouble, corticosteroids are almost universally a good option to get them out. But for too many decades, for too many patients, despite all the improvements we have made in better understanding the disease and developing some promising new treatments, we have yet to shed the inexorable toxicity in multiple organs of steroid dependence.” She continued, “Corticosteroids, even at low dose, may have broad-spectrum effects. But, in fact, so do many of the more ‘targeted’ agents. If all patients were lined up at the beginning of a study while being given azathioprine or a calcineurin inhibitor or belimumab at a stable, tolerable dose, you might see the same data if you tapered that agent down. What we really need is improved individualized guidance about when and how fast to remove immune modulators from stable patients with lupus without disturbing the balance that had been achieved in such a quiescent patient.”

Cedars-Sinai Medical Center

That enduring uncertainty was echoed by Daniel J. Wallace, MD, professor of medicine at Cedars-Sinai Medical Center, Los Angeles: “The take-home message from this interesting paper,” he commented, “is that current lupus biomarkers are not adequate. They do not guide the practitioner well enough, so that all too often medication regimens are tapered even though the risks are not really well known. Also, there is evidence in the literature that fibrosis and ‘damage’ progress even if acute phase reactants such as sedimentation rate, [C-reactive protein], complement 3 and 4, and anti-dsDNA are normal. We don’t have a good metric to detect them.”

Dr. Cho and colleagues’ study was funded by AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen, Merck Serono, GlaxoSmithKline, and UCB. Dr. Gladman disclosed consulting and/or research support from AbbVie, Amgen, Bristol-Myers Squibb, Eli Lilly, Janssen, Novartis, Pfizer, and UCB.

Use of A1c levels for the diagnosis of type 2 diabetes (T2D) in women younger than 50 years may lead to underdiagnosis, owing to the effects of menstrual blood loss on A1c readings, shows the first study of its kind.

The analysis estimates that an additional 17% of undiagnosed women younger than 50 years could be reclassified as having T2D, and that women under 50 had an A1c distribution that was markedly lower than that of men under 50, by a mean of 1.6 mmol/mol.

In a study that will be presented at this year’s annual meeting of the European Association for the Study of Diabetes (EASD), the researchers wanted to investigate whether a contributing factor to late diagnosis of T2D in women under 50 may be the difference in A1c levels due to hemoglobin replacement linked to menstrual blood loss.

The study was published online in Diabetes Therapy. “If the threshold for diagnosis of diabetes ... was lowered by 2 mmol/mol in women under the age of 50, an additional 17% of these women (approximately equivalent to 35,000 women in England and Wales) would be diagnosed with diabetes ... which may contribute to up to 64% of the difference in mortality rates between men/women with diabetes mellitus aged 16-50 years,” the researchers noted.

They added that A1c levels in women under 50 years were found to be consistently lower than those in men, and with A1c levels in women reaching the equivalent of those in men up to 10 years later, this “may result in delayed diagnosis of diabetes mellitus in premenopausal women.”

Noting that the study was observational, senior author Adrian Heald, MD, consultant endocrinologist, Salford (England) Royal NHS Foundation Trust, said that it “may be the case that prediabetes and type 2 diabetes in women are not being spotted because the set point needs to be slightly lower, but a systematic study sampling from the population of at-risk individuals is needed further to our findings.

“We also need to refer back to use of the glucose tolerance test, because A1c has been used for the past 15 years but it is not the gold standard,” added Dr. Heald. “Clinicians have often wondered if patients might be missed with A1c measurement, or even overdiagnosed.”

Lucy Chambers, PhD, from Diabetes UK, acknowledged that the research was valuable but added: “More research on sex differences in thresholds for a type 2 diagnosis is needed to inform any changes to clinical practice. In the meantime, we encourage clinicians to follow the current guidance of not ruling out type 2 diabetes based on a one-off A1c below the diagnostic threshold.”

But in support of greater understanding around the sex differences in A1c diagnostic thresholds, Dr. Chambers added: “Receiving an accurate and timely diagnosis ensures that women get the treatment and support needed to manage their type 2 diabetes and avoid long-term complications, including heart disease, where sex-based inequalities in care already contribute to poorer outcomes for women.” 
 

Effect of A1c reference range on T2D diagnosis and associated CVD

Compared with men, women with T2D have poorer glycemic control; a higher risk for cardiovascular (CV) complications; reduced life expectancy (5.3 years shorter vs. 4.5 years shorter); and a higher risk factor burden, such as obesity and hypertension at diagnosis.

In addition, T2D is a stronger risk factor for CV disease (CVD) in women than in men, and those aged 35-59 years who receive a diagnosis have the highest relative CV death risk across all age and sex groups.

The researchers pointed out that previous studies have observed differences in A1c relative to menopause, and they too found that “A1c levels rose after the age of 50 in women.”

However, they noted that the implication of differing A1c reference ranges on delayed diabetes diagnosis with worsening CV risk profile had not been previously recognized and that their study “[h]ighlights for the first time that, while 1.6 mmol/mol may appear only a small difference in terms of laboratory measurement, at population level this has implications for significant number of premenopausal women.”

The researchers initially observed the trend in local data in Salford, in the northwest of England. “These ... data highlighted that women seemed to be diagnosed with type 2 diabetes at an older age, so we wanted to examine what the source of that might be,” study author Mike Stedman, BSc, director, Res Consortium, Andover, England, said in an interview.

Dr. Stedman and his colleagues assessed the sex and age differences of A1c in individuals who had not been diagnosed with diabetes (A1c ≤ 48 mmol/mol [≤ 6.5%]). “We looked at data from other labs [in addition to those in Salford, totaling 938,678 people] to see if this was a local phenomenon. They could only provide more recent data, but these also showed a similar pattern,” he added.

Finally, Dr. Stedman, Dr. Heald, and their colleagues estimated the possible national impact by extrapolating findings based on population data from the UK Office of National Statistics and on National Diabetes Audit data for type 2 diabetes prevalence and related excess mortality. This brought them to the conclusion that T2D would be diagnosed in an additional 17% of women if the threshold were lowered by 2 mmol/mol, to 46 mmol/mol, in women under 50 years.
 

Lower A1c in women under 50 may delay T2D diagnosis by up to 10 years

The analysis found that the median A1c increased with age, with values in women younger than 50 years consistently being 1 mmol/mol lower than values in men. In contrast, A1c values in women over 50 years were equivalent to those in men.

However, at age 50 years, compared with men, A1c in women was found to lag by approximately 5 years. Women under 50 had an A1c distribution that was lower than that of men by an average of 1.6 mmol/mol (4.7% of mean; P < .0001), whereas this difference in individuals aged 50 years or older was less pronounced (P < .0001).

The authors wrote that “an undermeasurement of approximately 1.6 mmol/mol A1c in women may delay their diabetes ... diagnosis by up to 10 years.”

Further analysis showed that, at an A1c of 48 mmol/mol, 50% fewer women than men under the age of 50 could be diagnosed with T2D, whereas only 20% fewer women than men aged 50 years or older could be diagnosed with T2D.

Lowering the A1c threshold for diagnosis of T2D from 48 mmol/mol to 46 mmol/mol in women under 50 led to an estimate that an additional 35,345 undiagnosed women in England could be reclassified as having a T2D diagnosis.

The authors pointed out that “gender difference in adverse cardiovascular risk factors are known to be present prior to the development of [type 2] diabetes” and that “once diagnosed, atherosclerotic CVD prevalence is twice as high in patients with diabetes ... compared to those without a diagnosis.”

Dr. Heald added that there is always the possibility that other factors might be at play and that the work posed questions rather than presented answers.

Taking a pragmatic view, the researchers suggested that “one alternative approach may be to offer further assessment using fasting plasma glucose or oral glucose tolerance testing in those with A1c values of 46 or 47 mmol/mol.”

“In anyone with an early diagnosis of type 2 diabetes, in addition to dietary modification and especially if there is cardiovascular risk, then one might start them on metformin due to the cardiovascular benefits as well as the sugar-lowering effects,” said Dr. Heald, adding that “we certainly don’t want women missing out on metformin that could have huge benefits in the longer term.”

Dr. Stedman and Dr. Heald declared no support from any organization for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years; and no other relationships or activities that could appear to have influenced the submitted work. Dr. Chambers has declared no conflicts.

A version of this article appeared on Medscape.com.

Use of A1c levels for the diagnosis of type 2 diabetes (T2D) in women younger than 50 years may lead to underdiagnosis, owing to the effects of menstrual blood loss on A1c readings, shows the first study of its kind.

The analysis estimates that an additional 17% of undiagnosed women younger than 50 years could be reclassified as having T2D, and that women under 50 had an A1c distribution that was markedly lower than that of men under 50, by a mean of 1.6 mmol/mol.

In a study that will be presented at this year’s annual meeting of the European Association for the Study of Diabetes (EASD), the researchers wanted to investigate whether a contributing factor to late diagnosis of T2D in women under 50 may be the difference in A1c levels due to hemoglobin replacement linked to menstrual blood loss.

The study was published online in Diabetes Therapy. “If the threshold for diagnosis of diabetes ... was lowered by 2 mmol/mol in women under the age of 50, an additional 17% of these women (approximately equivalent to 35,000 women in England and Wales) would be diagnosed with diabetes ... which may contribute to up to 64% of the difference in mortality rates between men/women with diabetes mellitus aged 16-50 years,” the researchers noted.

They added that A1c levels in women under 50 years were found to be consistently lower than those in men, and with A1c levels in women reaching the equivalent of those in men up to 10 years later, this “may result in delayed diagnosis of diabetes mellitus in premenopausal women.”

Noting that the study was observational, senior author Adrian Heald, MD, consultant endocrinologist, Salford (England) Royal NHS Foundation Trust, said that it “may be the case that prediabetes and type 2 diabetes in women are not being spotted because the set point needs to be slightly lower, but a systematic study sampling from the population of at-risk individuals is needed further to our findings.

“We also need to refer back to use of the glucose tolerance test, because A1c has been used for the past 15 years but it is not the gold standard,” added Dr. Heald. “Clinicians have often wondered if patients might be missed with A1c measurement, or even overdiagnosed.”

Lucy Chambers, PhD, from Diabetes UK, acknowledged that the research was valuable but added: “More research on sex differences in thresholds for a type 2 diagnosis is needed to inform any changes to clinical practice. In the meantime, we encourage clinicians to follow the current guidance of not ruling out type 2 diabetes based on a one-off A1c below the diagnostic threshold.”

But in support of greater understanding around the sex differences in A1c diagnostic thresholds, Dr. Chambers added: “Receiving an accurate and timely diagnosis ensures that women get the treatment and support needed to manage their type 2 diabetes and avoid long-term complications, including heart disease, where sex-based inequalities in care already contribute to poorer outcomes for women.” 
 

Effect of A1c reference range on T2D diagnosis and associated CVD

Compared with men, women with T2D have poorer glycemic control; a higher risk for cardiovascular (CV) complications; reduced life expectancy (5.3 years shorter vs. 4.5 years shorter); and a higher risk factor burden, such as obesity and hypertension at diagnosis.

In addition, T2D is a stronger risk factor for CV disease (CVD) in women than in men, and those aged 35-59 years who receive a diagnosis have the highest relative CV death risk across all age and sex groups.

The researchers pointed out that previous studies have observed differences in A1c relative to menopause, and they too found that “A1c levels rose after the age of 50 in women.”

However, they noted that the implication of differing A1c reference ranges on delayed diabetes diagnosis with worsening CV risk profile had not been previously recognized and that their study “[h]ighlights for the first time that, while 1.6 mmol/mol may appear only a small difference in terms of laboratory measurement, at population level this has implications for significant number of premenopausal women.”

The researchers initially observed the trend in local data in Salford, in the northwest of England. “These ... data highlighted that women seemed to be diagnosed with type 2 diabetes at an older age, so we wanted to examine what the source of that might be,” study author Mike Stedman, BSc, director, Res Consortium, Andover, England, said in an interview.

Dr. Stedman and his colleagues assessed the sex and age differences of A1c in individuals who had not been diagnosed with diabetes (A1c ≤ 48 mmol/mol [≤ 6.5%]). “We looked at data from other labs [in addition to those in Salford, totaling 938,678 people] to see if this was a local phenomenon. They could only provide more recent data, but these also showed a similar pattern,” he added.

Finally, Dr. Stedman, Dr. Heald, and their colleagues estimated the possible national impact by extrapolating findings based on population data from the UK Office of National Statistics and on National Diabetes Audit data for type 2 diabetes prevalence and related excess mortality. This brought them to the conclusion that T2D would be diagnosed in an additional 17% of women if the threshold were lowered by 2 mmol/mol, to 46 mmol/mol, in women under 50 years.
 

Lower A1c in women under 50 may delay T2D diagnosis by up to 10 years

The analysis found that the median A1c increased with age, with values in women younger than 50 years consistently being 1 mmol/mol lower than values in men. In contrast, A1c values in women over 50 years were equivalent to those in men.

However, at age 50 years, compared with men, A1c in women was found to lag by approximately 5 years. Women under 50 had an A1c distribution that was lower than that of men by an average of 1.6 mmol/mol (4.7% of mean; P < .0001), whereas this difference in individuals aged 50 years or older was less pronounced (P < .0001).

The authors wrote that “an undermeasurement of approximately 1.6 mmol/mol A1c in women may delay their diabetes ... diagnosis by up to 10 years.”

Further analysis showed that, at an A1c of 48 mmol/mol, 50% fewer women than men under the age of 50 could be diagnosed with T2D, whereas only 20% fewer women than men aged 50 years or older could be diagnosed with T2D.

Lowering the A1c threshold for diagnosis of T2D from 48 mmol/mol to 46 mmol/mol in women under 50 led to an estimate that an additional 35,345 undiagnosed women in England could be reclassified as having a T2D diagnosis.

The authors pointed out that “gender difference in adverse cardiovascular risk factors are known to be present prior to the development of [type 2] diabetes” and that “once diagnosed, atherosclerotic CVD prevalence is twice as high in patients with diabetes ... compared to those without a diagnosis.”

Dr. Heald added that there is always the possibility that other factors might be at play and that the work posed questions rather than presented answers.

Taking a pragmatic view, the researchers suggested that “one alternative approach may be to offer further assessment using fasting plasma glucose or oral glucose tolerance testing in those with A1c values of 46 or 47 mmol/mol.”

“In anyone with an early diagnosis of type 2 diabetes, in addition to dietary modification and especially if there is cardiovascular risk, then one might start them on metformin due to the cardiovascular benefits as well as the sugar-lowering effects,” said Dr. Heald, adding that “we certainly don’t want women missing out on metformin that could have huge benefits in the longer term.”

Dr. Stedman and Dr. Heald declared no support from any organization for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years; and no other relationships or activities that could appear to have influenced the submitted work. Dr. Chambers has declared no conflicts.

A version of this article appeared on Medscape.com.

Use of A1c levels for the diagnosis of type 2 diabetes (T2D) in women younger than 50 years may lead to underdiagnosis, owing to the effects of menstrual blood loss on A1c readings, shows the first study of its kind.

The analysis estimates that an additional 17% of undiagnosed women younger than 50 years could be reclassified as having T2D, and that women under 50 had an A1c distribution that was markedly lower than that of men under 50, by a mean of 1.6 mmol/mol.

In a study that will be presented at this year’s annual meeting of the European Association for the Study of Diabetes (EASD), the researchers wanted to investigate whether a contributing factor to late diagnosis of T2D in women under 50 may be the difference in A1c levels due to hemoglobin replacement linked to menstrual blood loss.

The study was published online in Diabetes Therapy. “If the threshold for diagnosis of diabetes ... was lowered by 2 mmol/mol in women under the age of 50, an additional 17% of these women (approximately equivalent to 35,000 women in England and Wales) would be diagnosed with diabetes ... which may contribute to up to 64% of the difference in mortality rates between men/women with diabetes mellitus aged 16-50 years,” the researchers noted.

They added that A1c levels in women under 50 years were found to be consistently lower than those in men, and with A1c levels in women reaching the equivalent of those in men up to 10 years later, this “may result in delayed diagnosis of diabetes mellitus in premenopausal women.”

Noting that the study was observational, senior author Adrian Heald, MD, consultant endocrinologist, Salford (England) Royal NHS Foundation Trust, said that it “may be the case that prediabetes and type 2 diabetes in women are not being spotted because the set point needs to be slightly lower, but a systematic study sampling from the population of at-risk individuals is needed further to our findings.

“We also need to refer back to use of the glucose tolerance test, because A1c has been used for the past 15 years but it is not the gold standard,” added Dr. Heald. “Clinicians have often wondered if patients might be missed with A1c measurement, or even overdiagnosed.”

Lucy Chambers, PhD, from Diabetes UK, acknowledged that the research was valuable but added: “More research on sex differences in thresholds for a type 2 diagnosis is needed to inform any changes to clinical practice. In the meantime, we encourage clinicians to follow the current guidance of not ruling out type 2 diabetes based on a one-off A1c below the diagnostic threshold.”

But in support of greater understanding around the sex differences in A1c diagnostic thresholds, Dr. Chambers added: “Receiving an accurate and timely diagnosis ensures that women get the treatment and support needed to manage their type 2 diabetes and avoid long-term complications, including heart disease, where sex-based inequalities in care already contribute to poorer outcomes for women.” 
 

Effect of A1c reference range on T2D diagnosis and associated CVD

Compared with men, women with T2D have poorer glycemic control; a higher risk for cardiovascular (CV) complications; reduced life expectancy (5.3 years shorter vs. 4.5 years shorter); and a higher risk factor burden, such as obesity and hypertension at diagnosis.

In addition, T2D is a stronger risk factor for CV disease (CVD) in women than in men, and those aged 35-59 years who receive a diagnosis have the highest relative CV death risk across all age and sex groups.

The researchers pointed out that previous studies have observed differences in A1c relative to menopause, and they too found that “A1c levels rose after the age of 50 in women.”

However, they noted that the implication of differing A1c reference ranges on delayed diabetes diagnosis with worsening CV risk profile had not been previously recognized and that their study “[h]ighlights for the first time that, while 1.6 mmol/mol may appear only a small difference in terms of laboratory measurement, at population level this has implications for significant number of premenopausal women.”

The researchers initially observed the trend in local data in Salford, in the northwest of England. “These ... data highlighted that women seemed to be diagnosed with type 2 diabetes at an older age, so we wanted to examine what the source of that might be,” study author Mike Stedman, BSc, director, Res Consortium, Andover, England, said in an interview.

Dr. Stedman and his colleagues assessed the sex and age differences of A1c in individuals who had not been diagnosed with diabetes (A1c ≤ 48 mmol/mol [≤ 6.5%]). “We looked at data from other labs [in addition to those in Salford, totaling 938,678 people] to see if this was a local phenomenon. They could only provide more recent data, but these also showed a similar pattern,” he added.

Finally, Dr. Stedman, Dr. Heald, and their colleagues estimated the possible national impact by extrapolating findings based on population data from the UK Office of National Statistics and on National Diabetes Audit data for type 2 diabetes prevalence and related excess mortality. This brought them to the conclusion that T2D would be diagnosed in an additional 17% of women if the threshold were lowered by 2 mmol/mol, to 46 mmol/mol, in women under 50 years.
 

Lower A1c in women under 50 may delay T2D diagnosis by up to 10 years

The analysis found that the median A1c increased with age, with values in women younger than 50 years consistently being 1 mmol/mol lower than values in men. In contrast, A1c values in women over 50 years were equivalent to those in men.

However, at age 50 years, compared with men, A1c in women was found to lag by approximately 5 years. Women under 50 had an A1c distribution that was lower than that of men by an average of 1.6 mmol/mol (4.7% of mean; P < .0001), whereas this difference in individuals aged 50 years or older was less pronounced (P < .0001).

The authors wrote that “an undermeasurement of approximately 1.6 mmol/mol A1c in women may delay their diabetes ... diagnosis by up to 10 years.”

Further analysis showed that, at an A1c of 48 mmol/mol, 50% fewer women than men under the age of 50 could be diagnosed with T2D, whereas only 20% fewer women than men aged 50 years or older could be diagnosed with T2D.

Lowering the A1c threshold for diagnosis of T2D from 48 mmol/mol to 46 mmol/mol in women under 50 led to an estimate that an additional 35,345 undiagnosed women in England could be reclassified as having a T2D diagnosis.

The authors pointed out that “gender difference in adverse cardiovascular risk factors are known to be present prior to the development of [type 2] diabetes” and that “once diagnosed, atherosclerotic CVD prevalence is twice as high in patients with diabetes ... compared to those without a diagnosis.”

Dr. Heald added that there is always the possibility that other factors might be at play and that the work posed questions rather than presented answers.

Taking a pragmatic view, the researchers suggested that “one alternative approach may be to offer further assessment using fasting plasma glucose or oral glucose tolerance testing in those with A1c values of 46 or 47 mmol/mol.”

“In anyone with an early diagnosis of type 2 diabetes, in addition to dietary modification and especially if there is cardiovascular risk, then one might start them on metformin due to the cardiovascular benefits as well as the sugar-lowering effects,” said Dr. Heald, adding that “we certainly don’t want women missing out on metformin that could have huge benefits in the longer term.”

Dr. Stedman and Dr. Heald declared no support from any organization for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years; and no other relationships or activities that could appear to have influenced the submitted work. Dr. Chambers has declared no conflicts.

A version of this article appeared on Medscape.com.